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AU2003294831A1 - 4-substituted benzimidazoles and their use as inhibitors of gastric secretion - Google Patents

4-substituted benzimidazoles and their use as inhibitors of gastric secretion Download PDF

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Publication number
AU2003294831A1
AU2003294831A1 AU2003294831A AU2003294831A AU2003294831A1 AU 2003294831 A1 AU2003294831 A1 AU 2003294831A1 AU 2003294831 A AU2003294831 A AU 2003294831A AU 2003294831 A AU2003294831 A AU 2003294831A AU 2003294831 A1 AU2003294831 A1 AU 2003294831A1
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alkoxy
alkyl
hydrogen
hydroxy
cycloalkyl
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AU2003294831A
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Christof Brehm
Wilm Buhr
Vittoria Chiesa
Gerhard Grundler
Wolfgang Kromer
Andreas Palmer
Stefan Postius
Jorg Senn-Bilfinger
Wolfgang-Alexander Simon
Peter Jan Zimmermann
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Takeda GmbH
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Altana Pharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Description

WO 2004/054984 PCT/EP2003/014069 4-SUBSTITUTED BENZIMIDAZOLES AND THEIR USE AS INHIBITORS OF GASTRIC SECRETION Technical field The invention relates to novel compounds, which are used in the pharmaceutical industry as active compounds for the production of medicaments. Prior art In the European patent application 266326 (which corresponds to US Patent 5,106,862), benzimidazole derivatives having a very broad variety of substituents are disclosed, which are said to be active as anti ulcer agents. The international patent application WO 97147603 (which corresponds to US Patent 6,465,505) discloses benzimidazole derivatives substituted by a 2,6-dialkyl phenyl moiety, which are effective as inhibitors of the H*,K-ATPase. Summary of the invention The invention relates to compounds of the formula 1 R2 N
/
- R 1 (1) N in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1 -4C-alkylamino or 1-4C-alkylcarbonyloxy-I -4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminol-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31R32, the group SO 2 -NR31R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and WO 2004/054984 PCT/EP2003/014069 2 Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist ing of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, X is O (oxygen) or NH and Y has either the meaning -CH 2 -Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp R4 R5 / (gP) Z z wherein Z has the meaning -CHR8- or-CHR8-CHR9 where in, Ar and/or in the group gp R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo gen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7is hydrogen, 1-4C-alkyl or halogen, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-l1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- WO 2004/054984 PCT/EP2003/014069 3 alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1 4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-l1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1 4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes -CH 2 -Ar and R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-I-4C-alkyl, and the salts of these compounds. 1-4C-Alkyl represents straight-chain or branched alkyl groups having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group. 3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred. 3-7C-Cycloalkyl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be men tioned are the cyclopropylmethyl, the cyclohexylmethyl and the cyclohexylethyl group. 1-4C-Alkoxy represents groups, which in addition to the oxygen atom contain a straight-chain or bran ched alkyl group having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy group. 1-4C-Alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkoxy groups. Examples which may be mentioned are the methoxy methyl, the methoxyethyl group and the butoxyethyl group. 1-4C-Alkoxycarbonyl (-CO-1-4C-alkoxy) represents a carbonyl group, to which one of the aforemen tioned 1-4C-alkoxy groups is bonded. Examples which may be mentioned are the methoxycarbonyl (CH30-C(O)-) and the ethoxycarbonyl group (CH 3
CH
2 0-C(O)-).
WO 2004/054984 PCT/EP2003/014069 4 2-4C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 4 carbon atoms. Exam ples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl group (allyl group). 2-4C-Alkynyl represents straight-chain or branched alkynyl groups having 2 to 4 carbon atoms. Exam ples which may be mentioned are the 2-butynyl, 3-butynyl, and preferably the 2-propynyl, group (propargyl group). Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one or more fluorine atoms. An example which may be mentioned is the trifluoromethyl group. Hydroxy-1-4C-alkyl represents aforementioned 1-4C-alkyl groups, which are substituted by a hydroxy group. Examples which may be mentioned are the hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl group. 1-4C-Alkylcarbonyl represents a group, which in addition to the carbonyl group contains one of the afo rementioned 1-4C-alkyl groups. An example which may be mentioned is the acetyl group. Mono- or di-1-4C-alkylamino represents an amino group, which is substituted by one or by two - identi cal or different - groups from the aforementioned 1-4C-alkyl groups. Examples which may be men tioned are the dimethylamino, the diethylamino and the diisopropylamino group. Mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl represents a 1-4C-alkylcarbonyl group, which is substi tuted by a mono- or di-1-4C-alkylamino groups. Examples, which may be mentioned, are the dimethyl amino-methylcarbonyl and the dimethylamino-ethylcarbonyl group. Fluoro-2-4C-alkyl represents a 2-4C-alkyl groups, which is substituted by one or more fluorine atoms. An example which may be mentioned is the 2,2,2-trifluoroethyl group. Aryl-1-4C-alkoxy denotes an aryl-substituted 1-4C-alkoxy radical. An example which may be mentioned is the benzyloxy radical. Aryl-1-4C-alkoxy-1-4C-alkyl denotes one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned aryl-1-4C-alkoxy radicals. An example which may be mentioned is the benzyloxymethyl radical. Halogen within the meaning of the invention is bromo, chloro and fluoro.
WO 2004/054984 PCT/EP2003/014069 5 1-4C-Alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substi tuted by a further 1-4C-alkoxy group. Examples which may be mentioned are the groups 2-(methoxy)ethoxy (CH 3
-O-CH
2
-CH
2 -O-) and 2-(ethoxy)ethoxy (CH 3
-CH
2
-O-CH
2
-CH
2 -O-). 1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkoxy-1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkoxy groups. An example which may be mentioned is the group 2-(methoxy)ethoxymethyl (CH 3
-O-CH
2
-CH
2
-O-CH
2 -). Fluoro-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substi tuted by a fluoro-1-4C-alkoxy group. Fluoro-1-4C-alkoxy in this case represents one of the aforemen tioned 1-4C-alkoxy groups, which is completely or mainly substituted by fluorine. Examples of com pletely or mainly fluoro-substituted 1-4C-alkoxy groups which may be mentioned are the 1,1,1,3,3,3 hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1,1,1-trifluoro-2-propoxy, the perfluoro-tert butoxy, the 2,2,3,3,4,4,4-heptafluoro-1 -butoxy, the 4,4,4-trifluoro-1 -butoxy, the 2,2,3,3,3-penta fluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy group. 1-7C-Alkyl represents straight-chain or branched alkyl groups having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neo hexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobu tyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group. 2-4C-Alkenyloxy represents groups, which in addition to the oxygen atom contain one of the abovemen tioned 2-4C-alkenyl groups. Examples, which may be mentioned, are the 2-butenyloxy, 3-butenyloxy, 1 propenyloxy and the 2-propenyloxy group (allyloxy group). Carboxy-1-4C-alkyl represents 1-4C-alkyl groups which are substituted by a carboxyl group. Examples, which may be mentioned, are the carboxymethyl and the 2-carboxyethyl group. 1-4C-Alkoxycarbonyl-1-4C-alkyl represents 1-4C-alkyl groups, which are substituted by one of the abovementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the Methoxy carbonylmethyl and the ethoxycarbonylmethyl group. Aryl-1-4C-alkyl denotes an aryl-substituted 1-4C-alkyl radical. An example which may be mentioned is the benzyl radical. 1-4C-Alkylcarbonylamino represents an amino group to which a 1-4C-alkylcarbonyl group is bonded. Examples which may be mentioned are the propionylamino (C 3
H
7 C(O)NH-) and the acetylamino group (acetamido group) (CH 3 C(0)NH-).
WO 2004/054984 PCT/EP2003/014069 6 1-4C-Alkoxycarbonylamino represents an amino group, which is substituted by one of the aforemen tioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the ethoxycarbonylamino and the methoxycarbonylamino group. 1-4C-Alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group, to which one of the aforementioned 1-4C-alkoxy-1-4C-alkoxy groups is bonded. Examples which may be mentioned are the 2-(methoxy) ethoxycarbonyl (CH 3
-O-CH
2
CH
2 -O-CO-) and the 2-(ethoxy)ethoxycarbonyl group (CH 3
CH
2
-O-CH
2
CH
2 O-CO-). 1-4C-Alkoxy-1-4C-alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl groups. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonylamino and the 2-(ethoxy)ethoxycarbonylamino group. 2-7C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 7 carbon atoms. Exam ples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl, the 2-propenyl (allyl) and the vinyl group. The aforementioned 2-4C-alkenyl groups are preferred. 2-7C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 7 carbon atoms. Exam ples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl, the 2-propenyl (allyl) and the vinyl group. The aforementioned 2-4C-alkenyl groups are preferred. Oxo-substituted 1-4C-alkoxy represents a 1-4C-alkoxy group, which instead of a methylene group con tains a carbonyl group. An example which may be mentioned is the 2-oxopropoxy group. 3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cyclo heptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred. 3-7C-Cycloalkyl-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is sub stituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropylmethoxy, the cyclobutylmethoxy and the cyclohexylethoxy group. Hydroxy-1-4C-alkoxy represents aforementioned 1-4C-alkoxy groups, which are substituted by a hy droxy group. A preferred example which may be mentioned is the 2-hydroxyethoxy group. 1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxy groups. A preferred exam ple which may be mentioned is the methoxyethoxyethoxy group. 3-7C-Cycloalkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkoxy groups. Examples which may be mentioned are the cyclopropoxymethoxy, the cyclobutoxymethoxy and the cyclohexyloxyethoxy group.
WO 2004/054984 PCT/EP2003/014069 7 3-7C-Cycloalkyl-1-4C-alkoxy-l-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl-l1-4C-alkoxy groups. Examples which may be mentioned are the cyclopropylmethoxyethoxy, the cyclobutylmethoxyethoxy and the cyclohexy lethoxyethoxy group. 1-4C-Alkylcarbonyloxy represents a 1-4C-alkylcarbonyl group which is bonded to an oxygen atom. An example which may be mentioned is the acetoxy group (CH 3 CO-O-). 1-4C-Alkylcarbonyloxy-l-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkylcarbonyloxy groups. An example which may be mentioned is the acetoxymethyl group (CH 3
CO-O-CH
2 ). Halo-1 -4C-alkoxy represents 1-4C-alkoxy groups which are completely or mainly substituted by halo gen. "Mainly" in this connection means that more than half of the hydrogen atoms in the 1-4C-alkoxy groups are replaced by halogen atoms. Halo-1-4C-alkoxy groups are primarily chloro- and/or in particu lar fluoro-substituted 1-4C-alkoxy groups. Examples of halogen-substituted 1-4C-alkoxy groups which may be mentioned are the 2,2,2-trichloroethoxy, the hexachloroisopropoxy, the pentachloroisopropoxy, the 1,1,1-trichloro-3,3,3-trifluoro-2-propoxy, the 1,1,1-trichloro-2-methyl-2-propoxy, the 1,1,1-trichloro-2 propoxy, the 3-bromo-1,1,1-trifluoro-2-propoxy, the 3-bromo-1,1,1-trifluoro-2-butoxy, the 4-bromo 3,3,4,4-tetrafluoro-l-butoxy, the chlorodifluoromethoxy, the 1,1,1,3,3,3-hexafluoro-2-propoxy, the 2 trifluoromethyl-2-propoxy, the 1,1,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4 heptafluoro-1 -butoxy, the 4,4,4-trifluoro-1 -butoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluo romethoxy and preferably the difluoromethoxy group. Mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy represents a 1-4C-alkylcarbonyloxy group, which is substituted by one of the aforementioned mono- or di-1-4C-alkylamino groups. Examples, which may be mentioned, are the dimethylamino-methylcarbonyloxy and the dimethylamino-ethylcarbonyloxy group. 1-4C-Alkoxy-1-4C-alkylcarbonyloxy represents one of the aforementioned 1-4C-alkylcarbonyloxy radi cals which is substituted by one of the aforementioned 1-4C-alkoxy groups. An example, which may be mentioned, is the methoxymethylcarbonyloxy group. Possible salts of compounds of the formula 1 or 2 - depending on substitution - are especially all acid addition salts. Particular mention may be made of the pharmacologically tolerable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4 hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fu maric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, WO 2004/054984 PCT/EP2003/014069 8 methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are used in salt preparation - de pending on whether a mono- or polybasic acid is concerned and on which salt is desired - in an equimo lar quantitative ratio or one differing therefrom. Pharmacologically intolerable salts, which can initially be obtained, for example, as process products in the production of the compounds according to the invention on the industrial scale, are converted into the pharmacologically tolerable salts by processes known to the person skilled in the art. It is known to the person skilled in the art that the compounds according to invention and their salts, if, for example, they are isolated in crystalline form, can contain various amounts of solvents. The inven tion therefore also comprises all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I. One embodiment (embodiment a) comprises compounds of the formula 1, in which R1 is mono- or di-1-4C-alkylamino R2, R3, X and Y have the meanings given above in the summary of the invention with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes -CH 2 -Ar and R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-1-4C-alkyl, and the salts of these compounds. One embodiment (embodiment b) comprises compounds of the formula 1, in which R1 is 1-4C-alkylcarbonyloxy-1-4C-alkyl and R2, R3, X and Y have the meanings given above in the summary of the invention and the salts of these compounds. Another embodiment (embodiment c) comprises compounds of the formula 1, in which R2 is hydroxy or 1-4C-alkoxy and R1, R3, X and Y have the meanings given above in the summary of the invention and the salts of these compounds. Another embodiment (embodiment d) comprises compounds of the formula 1, in which R3 is cyano, the group SO 2 -NR31R32 or the group Het and where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and WO 2004/054984 PCT/EP2003/014069 9 Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist ing of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-l1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1 -4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, where R1, R2, X and Y have the meanings given above in the summary of the invention and the salts of these compounds. Another embodiment (embodiment e) comprises compounds of the formula 1, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C alkyl, R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminol-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C alkoxy-1-4C-alkyl R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-l-4C-alkyl, 1-4C alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-l1-4C-alkoxy-l1-4C-alkyl or the group -CO-NR31 R32, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C cycloalkyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1 -4C-alkylpiperazino, morpholino, aziridino or azetidino group, X is O (oxygen) or NH and Y has either the meaning -CH 2 -Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, WO 2004/054984 PCT/EP2003/014069 10 or Y denotes the group gp R4 R5 /(gP) z wherein Z has the meaning -CHR8- or -CHR8-CHR9 where in Ar and/or in the group gp R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo gen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxyl 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1 4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-l1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1 4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes -CH 2 -Ar, and the salts of these compounds.
WO 2004/054984 PCT/EP2003/014069 11 Another embodiment (embodiment f) comprises compounds of the formula 1, in which Ri is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C alkyl, R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminol-4C-alkylcarbonyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl, R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the group -CO-N R31 R32, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, X is O (oxygen) or NH and Y has either the meaning -CH 2 -Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp R4 R5 / (gp) z wherein Z has the meaning -CHR8- or-CHR8-CHR9 where in Ar and/or in the group gp R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo gen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, WO 2004/054984 PCT/EP2003/014069 12 R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1 -4C-alkylcarbonyloxy or l-4C-alkoxy-1 -4C-alkoxycarbonylamino, R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1 -4C-alkylcarbonyloxy or l-4C-alkoxy- -4C-alkoxycarbonylamino and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes -CH 2 -Ar, and the salts of these compounds. In one aspect, the invention relates to compounds of the formula la R2 I R3 N / RI N .X (1 a) Ar in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-l1-4C-alkyl, mono- or di-l1-4C-alkylamino or 1-4C-alkylcarbonyloxy-l1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-l-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminol-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-l1-4C alkoxy-l1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-l-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-l-4C-alkyl, 1-4C alkoxy-l1-4C-alkyl, 1-4C-alkoxy-l1-4C-alkoxy-l1-4C-alkyl, fluoro-1-4C-alkoxy-l1-4C-alkyl, cyano, the group -CO-NR31R32, the group SO 2 -NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-l1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, WO 2004/054984 PCT/EP2003/014069 13 or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist ing of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1 -4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, X is O (oxygen) or NH and Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, ben zimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, where R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo gen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C alkoxy-1 -4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7is hydrogen, 1-4C-alkyl or halogen, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes -CH 2 -Ar and R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-1-4C-alkyl, and the salts of these compounds In another aspect, the invention relates to compounds of the formula la in which WO 2004/054984 PCT/EP2003/014069 14 R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C alkyl, R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminol-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C alkoxy-1-4C-alkyl R3 is fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1 4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C cycloalkyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, X is O (oxygen) or NH and Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, ben zimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, where R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo gen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7is hydrogen, 1-4C-alkyl or halogen, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds. In another aspect, the invention relates to compounds of the formula la in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C alkyl, WO 2004/054984 PCT/EP2003/014069 15 R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminol-4C-alkylcarbonyl, hydroxy-l1-4C-alkyl or fluoro-2-4C-alkyl R3 is fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1 4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, X is O (oxygen) or NH and Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, ben zimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, where R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo gen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-l1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7is hydrogen, 1-4C-alkyl or halogen, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds. In another aspect, the invention relates to compounds of the formula lb R2 / R3- -.. jN R4 N R5 / X (1b) Zin which in which WO 2004/054984 PCT/EP2003/014069 16 R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1 -4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminol-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-l-4C-alkyl, 1-4C alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31 R32,, the group SO 2 -NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-l-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist ing of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1 -4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hy droxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1 4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-l -4C alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O (oxygen) or NH and Z has the meaning -CHR8- or-CHR8-CHR9 where R8 is hydrogen, l-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-l1-4C-alkoxy, 1-4C-alkoxy-l1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C- WO 2004/054984 PCT/EP2003/014069 17 alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1 4C-alkylcarbonyloxy, R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-l1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1 4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds. In another aspect, the invention relates to compounds of the formula lb in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C alkyl, R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminol-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C alkoxy-1-4C-alkyl R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C cycloalkyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hy droxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1 4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, WO 2004/054984 PCT/EP2003/014069 18 X is O (oxygen) or NH and Z has the meaning -CHR8- or-CHR8-CHR9 where R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-l1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-l1-4C-alkoxy, 1-4C-alkoxy-l1-4C-alkoxy-l1-4C-alkoxy, 3-7C-cycloalkoxy-l1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-l1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1 4C-alkylcarbonyloxy, R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-l1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-l1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1 4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds. In another aspect, the invention relates to compounds of the formula lb in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C alkyl, R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-l-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1 -4C-alkylaminol-4C-alkylcarbonyl, hydroxy-l1-4C-alkyl or fluoro-2-4C-alkyl, R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-l1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-l1-4C-alkyl or 1-4C-alkoxy-l1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-l1-4C-alkyl, halogen, hy- WO 2004/054984 PCT/EP2003/014069 19 droxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1 4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-l1-4C alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O (oxygen) or NH and Z has the meaning -CHR8- or-CHR8-CHR9 where R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-l1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-l1-4C-alkoxy-l1-4C-alkoxy, 3-7C-cycloalkoxy-l1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1 -4C-alkylcarbonyloxy or 1-4C-alkoxy-1 -4C-alkoxycarbonylamino, R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-l1-4C-alkoxy, 1-4C-alkoxy-l1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1-4C-alkylcarbonyloxy or 1-4C-alkoxy-l1-4C-alkoxycarbonylamino, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds. The compounds of the formula lb have up to three chiral centers in the parent structure. The invention thus relates to all conceivable stereoisomers in any desired mixing ratio to one another, including the pure enantiomers, which are a preferred subject of the invention. Among the compounds of the formula l a, preferred compounds are those of the formula la-1 R2 R3 N /N / -R1 N X (la-1) R5 R4 in which WO 2004/054984 PCT/EP2003/014069 20 R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-I-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R2 is hydrogen,I-4C-alkyl, hydroxy, 1-4C-alkoxy or aryl-1-4C-alkoxy-1-4C-alkyl R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO NR31R32, the group SO 2 -NR31R32 or the group Het, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or amino and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist ing of oxadiazol, dihydrooxazol and dihydroimidazol, where R33 is hydrogen or 1-4C-alkyl, R34 is hydrogen or 1-4C-alkyl R35 is hydrogen or 1-4C-alkyl R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoromethyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino or 1 4C-alkoxy-1 -4C-alkoxycarbonylamino, R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and X is O (oxygen) or NH, and the salts of these compounds. Among the compounds of the formula la, particularly preferred compounds are those of the formula la-1 where R1 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl, R2 is hydrogen or 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, or the group -CO NR31R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-I-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1 -4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoromethyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino or 1 4C-alkoxy-1-4C-alkoxycarbonylamino, R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and WO 2004/054984 PCT/EP2003/014069 21 X is O (oxygen) or NH, and the salts of these compounds. Particularly preferred compounds of the formula la-1 are those, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-l-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-l-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, R4 is 1-4C-alkyl or 1-4C-alkylcarbonylamino, R5 is 1-4C-alkyl, X is O (oxygen) or NH, and their salts. Among the compounds of the formula l b, compounds of the formula 1 b-1 R2 / / RI R4 N R5 / X (lb-1) R8 are preferred. Preferred exemplary compounds of the formula 1 b-1 are those, in which RI is 1-4C-alkyl or 3-7C-cycloalkyl, R2 is hydrogen or 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-l1-4C-alkyl, 1-4C-alkoxy-l1-4C-alkoxy-1 -4C-alkyl or the group -CO-NR31 R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-l-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen or 1-4C-alkyl, WO 2004/054984 PCT/EP2003/014069 22 R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-l1-4C alkoxy, hydroxy-l1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3 7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C alkoxycarbonylamino or 1-4C-alkoxy-l1-4C-alkylcarbonyloxy X is O (oxygen) or NH, and their salts. Particularly preferred exemplary compounds of the formula lb-1 are those, in which R1 is 1-4C-alkyl, R2 is hydrogen or 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-I-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1 -4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-l1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen or alkyl, R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-l1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3 7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C alkoxycarbonylamino or 1-4C-alkoxy-l1-4C-alkylcarbonyloxy X is 0 (oxygen) or NH, and their salts. Still particularly preferred exemplary compounds of the formula 1 b-1 are those, in which R1 is 1-4C-alkyl, R2 is hydrogen or 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-l1-4C-alkyl, or where WO 2004/054984 PCT/EP2003/014069 23 R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen, R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3 7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-l1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy X is O (oxygen) or NH, and their salts. Preferred compounds are those of the formula la-1. Particularly preferred are the compounds given as final products of formula 1 in the examples, and the salts of these compounds. The compounds according to the invention can be synthesised from corresponding starting com pounds, for example according to the reaction schemes given below. The synthesis is carried out in a manner known to the expert, for example as described in more detail in the following examples. The starting compounds are known, for example from M. W. Lovell, S. G. Schulman, Anal Chem. 1983, 55, 963-965 (e. g. 4-bromo-6-nitro-1,2-phenylenediamine). 6-Halo,4-nitro-substituted benzimida zoles are known in literature, for example 6-chloro-2-methyl-4-nitro-1 (3)H-benzimidazole (Gillespie et al., J. Org. Chem. 1960, 25, 942) or they can be prepared using analogous process steps. 1,2 Epoxyindan is described for example in W. F. Whitmore; A. I. Gebhart, J. Am. Chem. Soc. 1942, 64, 912. In general, substituted alkyl-, alkoxy- or halogeno-epoxyindanes can be prepared from the corre sponding substituted indenes by methods known from literature (e.g. epoxidation). The compounds of the general formula la can be obtained by reacting substituted benzimidazoles of formula I with com pounds of formula II as depicted in scheme 1. Scheme 1: R2 R2 R 3 N R +A H a l R 3 N R 1 " : N/>-R1 Ar N XH X I, X = O, NH II Ar la, X= O, NH WO 2004/054984 PCT/EP2003/014069 24 Analogously, compounds of the general formula lb are obtained by reacting substituted benzimidazoles of formula I with epoxyindanes III, carrying any desired substituent R4 and R5 (cf. scheme 2 for a com pound lb-1). Scheme 2: R2 R2 / R4 R3 N R3 N RI +
-
R4 / N N XH R5 rac. R5 / , I, X = O, NH III OH lb-1, X = O, NH The reaction steps outlined above are carried out in a manner known per se, e. g. as described in more detail in the examples. The derivatization, if any, of the compounds obtained according to the above Scheme 1 and 2 (e.g. conversion of a group R3 into another group R3, or of R2 = H into another group R2, or conversion of the hydroxyl group into an alkoxy or ester group) is likewise carried out in a man ner known per se. If compounds where R3 = -CO-1-4C-alkoxy or R3 = -CO-NR31 R32 are desired, an appropriate derivatization can be performed in a manner known per se (e. g. metal catalysed carbonyla tion of the corresponding bromo compound or conversion of an ester into an amide) at the stage of the benzimidazoles of formula I (scheme 1 and 2) or more conveniently at a later point in time. The following examples serve to illustrate the invention in greater detail without restricting it. Likewise, further compounds of the formula 1 whose preparation is not described explicitly can be prepared in an analogous manner or in a manner familiar per se to the person skilled in the art using customary proc ess techniques. The abbreviation min stands for minute(s), h for hour(s) and m.p. for melting point.
WO 2004/054984 PCT/EP2003/014069 25 Examples I.Starting materials A. 2-Benzyloxy-4-bromo-6-nitro-aniline To a suspension of 50 g (325 mmol) 2-amino-3-nitrophenol, 45 g (325 mmol) potassium carbonate and 2 g (13 mmol) sodium iodide in 400 ml ethanol were added 47 ml (408 mmol) benzyl chloride and the mixture was heated to 80 oC. After 2 h, the reaction mixture was cooled down and the solvent was evaporated. The residue was dissolved in ethyl acetate and extracted with water. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Coevaporation with dichloromethane led to a dark brown oily residue which was dissolved in 400 ml acetonitrile. After addition of 63.4 g (356 mmol) N-bromosuccinimide, the reaction mixture was refluxed for 1 h. After cooling down, 400 g of silica gel were added and the mixture was evaporated to dryness. The resulting solid was purified by column chromatography on silica gel using ethyl acetate:light petroleum ether (4:1). Evaporation of the eluent left a solid which was recrystallized from ethyl acetate/n-heptane to give 62 g (59 %) of the title com pound as a red solid (m.p. 90 oC). B. N-Acetyl-N-(2-benzyloxy-4-bromo-6-nitro-phenyl)-acetamide A suspension of 20 g (62 mmol) 2-benzyloxy-4-bromo-6-nitro-aniline in 120 ml acetic anhydride and 2 ml methanesulphonic acid was heated to 120 oC. After complete reaction (15 min), excess acetic anhy dride was evaporated. The residue was dissolved in dichloromethane/water and neutralized with 6N aqueous sodium hydroxide. The organic layer was separated, dried over anhydrous magnesium sul phate and evaporated. Crystallization of the residue from ethyl acetate/n-heptane yielded 23.2 g (92 %) of the title compound as a beige solid (m.p. 148 'C). C. N-(2-Amino-6-benzyloxy-4-bromo-phenyl)-acetamide A suspension of 23 g (56 mmol) N-acetyl-N-(2-benzyloxy-4-bromo-6-nitro-phenyl)-acetamide, 5.5 g (34 mmol) iron(Ill) chloride and 13.8 g activated charcoal in 600 ml methanol was heated to reflux. To the reaction mixture were added 28 ml hydrazine hydrate (95 %) to maintain gentle reflux. After complete reaction (2 h), the mixture was cooled down and filtered through celite. The filter cake was washed thoroughly with dichloromethane/methanol and the filtrate was evaporated to dryness. The residue was partitioned between dichloromethane/methanol and water. The organic layer was washed with brine, dried over anhydrous magnesium sulphate and evaporated. The residue was recrystallized from boiling ethyl acetate/n-heptane to give 12.3 g (65 %) of the title compound as a colourless solid (m.p. 185 oC). D. N-(2-Benzyloxy-4-bromo-6-dimethylamino-phenyl)-acetamide A suspension of 5.0 g (15 mmol) N-(2-amino-6-benzyloxy-4-bromo-phenyl)-acetamide in 80 ml metha nol and 34 ml formaldehyde (37 %) was acidified with saturated methanolic hydrogen chloride to give a clear yellow solution. To the solution were added 1.5 g (24 mmol) sodium cyanoborohydride in small portions. After complete reaction (15 min), the mixture was neutralized with aqueous sodium hydrogen WO 2004/054984 PCT/EP2003/014069 26 carbonate and extracted with dichloromethane. The organic layer was dried over anhydrous magne sium sulphate and evaporated. Crystallization of the residue from ethyl acetate/n-heptane yielded 4.3 g (79 %) of the title compound as a colourless solid (m.p. 177 0C). E. 4-Benzyloxy-6-bromo-1,2-dimethyl-1 H-benzimidazole A suspension of 26.2 g (72 mmol) N-(2-benzyloxy-4-bromo-6-dimethylamino-phenyl)-acetamide in 180 ml phosphoryl chloride was heated to 70 'C for 24 h. After the reaction was complete, excess phos phoryl chloride was evaporated. The residue was suspended in dichloromethane and carefully neutral ized with 6N aqueous potassium hydroxide and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Crystallization of the residue from ethyl acetate yielded 15.1 g (63 %) of the title compound as a colourless solid (m.p. 177-179 0C). F. Ethyl 4-hydroxy-1,2-dimethyl-1H-benzimidazole-6-carboxylate A suspension of 12.0 g (37 mmol) ethyl 4-benzyloxy-1,2-dimethyl-lH-benzimidazole-6-carboxylate in 100 ml ethanol was hydrogenated over I g 10% Pd/C (50 0C, 5 bar H 2 ) for 16 h. The catalyst was fil tered off and the filtrate was evaporated. The residue was crystallized from ethanol/diethyl ether to give 5.91 g (69 %) of the title compound as a colourless solid (m.p. 272-273 'C). G. Methyl 4-hydroxy-1,2-dimethyl-1H-benzimidazole-6-carboxylate A suspension of 8.5 g (27 mmol) methyl 4-benzyloxy-1,2-dimethyl-lH-benzimidazole-6-carboxylate in 100 ml methanol was hydrogenated over 0.7 g 10% Pd/C (30 0C, 1 bar H 2 ) for 2 h. The catalyst was filtered off, washed several times with hot methanol and the filtrate was evaporated. The residue was crystallized from methanol/diethyl ether to give 6 g (99 %) of the title compound as a colourless solid (m.p. 286 oC). H. 4-Hydroxy-6-methoxymethyl-1,2-dimethyl-1lH-benzimidazole A solution of 1.2 g (4.1 mmol) 4-benzyloxy-6-methoxymethyl-1,2-dimethyl-1H-benzimidazole in 12 ml methanol was hydrogenated over 0.12 g 10% Pd/C (1 bar H 2 ) for 16 h. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from ethyl acetate/light petroleum ether to give 0.83 g (99 %) of the title compound as a colourless solid (m.p. 219-220 oC). I. 6-(N,N-Dimethylaminocarbonyl)-4-hydroxy-1,2-dimethyl-1lH-benzimidazole A solution of 2.3 g (7.1 mmol) 4-benzyloxy-6-(N,N-dimethylaminocarbonyl)-1,2-dimethyl-1lH benzimidazole in 80 ml methanol was hydrogenated over 0.3 g 10% Pd/C (1 bar H 2 ) for 16 h. The cata lyst was filtered off and the filtrate was evaporated. The residue was crystallized from acetone to give 1.2 g (71 %) of the title compound as a colourless solid (m.p. 248 0C).
WO 2004/054984 PCT/EP2003/014069 27 J. 6-Bromo-2-methyl-4-nitro-1(3)H-benzimidazole To a suspension of 65 g (0.28 mol) 5-bromo-3-nitro-1,2-phenylenediamine in 600 ml ethanol were added 140 ml 5N hydrochloric acid. The reaction mixture was hetaed to reflux and 58 ml (0.56 mol) 2,4 pentanedione were added in one portion. After 1 h, the mixture was cooled down, poured into 500 ml water and neutralized with conc. ammonia. The precipitate was collected, washed thoroughly with water and dried over phosphorus pentoxide to give 70.8 g (99 %) of the title compound (m.p. 229-231 0C). K. 6-Bromo-4-nitro-1(3)H-benzimidazole To a suspension of 14.25 g (61.4 mmol) 5-bromo-3-nitro-1,2-phenylenediamine in 120 ml 4N hydro chloric acid were added 4.65 ml (123 mmol) formic acid. The reaction mixture was heated to 120 oC. After 1.5 h, the mixture was cooled down and neutralized with conc. ammonia. The precipitate was collected, washed with water and dried over phosphorus pentoxide. Recrystallization from ethanol and activated charcoal yielded 9.79 g (66 %) of the title compound (m.p. 249 'C). L. 6-Bromo-2-methoxymethyl-4-nitro-1(3)H-benzimidazole A suspension of 1 g (4.3 mmol) 5-bromo-3-nitro-1,2-phenylenediamine in 4 ml methoxyacetic acid was heated to 110 'C for 16 h. The mixture was poured into icewater, neutralized with 6N aqueous sodium hydroxide and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate and activated charcoal yielded 0.9 g (73 %) of the title compound as a colourless solid (m.p. 173 0C). M. 6-Bromo-1-methyl-4-nitro-1H-benzimidazole A suspension of 5.12 g (21.2 mmol) 6-bromo-4-nitro-1(3)H-benzimidazole and 4.6 g (33.3 mmol) po tassium carbonate in 200 ml acetone was stirred 30 min and 1.54 ml (24.7 mmol) methyl iodide were then added. After stirring 18 h at ambient temperature, excess solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was separated, dried over an hydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate yielded 2.7 g (50 %) of the title compound as a colourless solid (m.p. 198 °C). N. 6-Bromo-2-methoxymethyl-1l-methyl-4-nitro-1H-benzimidazole To a suspension of 13 g (45.4 mmol) 6-bromo-2-methoxymethyl-4-nitro-1(3)H-benzimidazole and 12.6 g (90.9 mmol) potassium carbonate in 130 ml acetone were added 6.8 g (47.7 mmol) methyl iodide and the mixture was stirred for 18 h at ambient temperature. The thick suspension was poured into 200 ml water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from diisopropyl ether yielded 13.6 g (99 %) of the title compound as a yellow solid (m.p. 145-147 0C).
WO 2004/054984 PCT/EP2003/014069 28 0. 1-Benzyloxymethyl-6-bromo-2-methyl-4-nitro-1H-benzimidazole To a suspension of 0.26 g (6.4 mmol) sodium hydride (60 % dispersion in mineral oil) in 10 ml N,N dimethylformamide was slowly added a solution of 1.5 g (5.9 mmol) 6-bromo-2-methyl-4-nitro-1(3)H benzimidazole in 5 ml N,N-dimethylformamide at 0 'C. After 1 h at 0 'C, 2.29 g (8.8 mmol) benzyloxy methylchloride (60 %) were added over 20 min. When the reaction was finished (1 h), 10 ml water were carefully added and the mixture was partitioned between dichloromethane and water. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:triethylamine (95:5) gave an oil which was crystallized from diisopropyl ether to yield 1.16 g (53 %) of the title compound as a yellow solid (m.p. 106-109°C). P. 6-Bromo-1,2-dimethyl-4-nitro-IH-benzimidazole To a suspension of 4.3 g (107 mmol) sodium hydride (60 % dispersion in mineral oil) in 25 ml N,N dimethylformamide was slowly added a solution of 25 g (98 mmol) 6-bromo-2-methyl-4-nitro-1(3)H benzimidazole in 100 ml N,N-dimethylformamide at 0 *C. After 30 min at 0 oC, 15.2 g (107 mmol) methyl iodide were added over 20 min. When the reaction was finished (45 min), 200 ml water were carefully added and the mixture was stirred 1 h at ambient temperature. The precipitate was collected, washed thoroughly with water and dried over phosphorus pentoxide. Recrystallization from methanol yielded 19.6 g (74 %) of the title compound as a colourless solid (m.p. 193-195 'C). Q. 4-Amino-6-bromo-l-methyl-1H-benzimidazole To a suspension of 10 g (39 mmol) 6-bromo-1-methyl-4-nitro-1H-benzimidazole in 100 ml methanol were added 7.6 g (46.9 mmol) iron(Ill) chloride and 2.5 g activated charcoal. The reaction mixture was heated to 80 oC and 9.5 ml hydrazine hydrate (95 %) were slowly added. After refluxing 2 h, a further amount of 2 ml hydrazine hydrate (95 %) was added. After 5 h, the hot reaction mixture was filtered through celite and the filter cake was washed with methanol and dichloromethane. The filtrate was evaporated to leave a solid, which was purified by column chromatography on silica gel using tolu ene:dioxane:methanol (6:3.6:0.4). Crystallization from diisopropyl ether yielded 6.8 g (77 %) of the title compound as a light yellow solid (m.p. 170 'C). R. 4-Amino-6-bromo-2-methoxymethyl-1-methyl-I H-benzimidazole To a suspension of 8.5 g (28.3 mmol) 6-bromo-2-methoxymethyl-1-methyl-4-nitro-IH-benzimidazole in 150 ml methanol were added 5.51 g (34 mmol) iron(lll) chloride, 2.5 g activated charcoal and 6.9 ml hydrazine hydrate (95 %). After refluxing 2 h, a further amount of 4 ml hydrazine hydrate (95 %) was added. After 4 h, the hot reaction mixture was filtered through celite and the filter cake was washed with methanol and dichloromethane. The filtrate was evaporated and the residue was purified by column chromatography on silica gel using dichloromethane:methanol (20:1). Crystallization from diisopropyl ether yielded 5.5 g (72 %) of the title compound as a colourless solid (m.p. 138-140 C).
WO 2004/054984 PCT/EP2003/014069 29 S. 4-Amino-1l-benzyloxymethyl-6-bromo-2-methyl-1H-benzimidazole To a suspension of 10 g (26.6 mmol) 1-benzyloxymethyl-6-bromo-2-methyl-4-nitro-IH-benzimidazole and 1 g activated charcoal in 150 ml methanol were added 5.2 g (31.9 mmol) iron(Ill) chloride and 6.5 ml hydrazine hydrate (95 %). After refluxing 1 h, a further amount of 3 ml hydrazine hydrate (95 %) was added. After 6 h, the hot reaction mixture was filtered through celite and the filter cake was washed with hot methanol. The filtrate was evaporated to leave a yellow solid which was purified by column chroma tography on silica gel using dichloromethane:methanol (9:1). Crystallization from diisopropyl ether yielded 6.68 g (73 %) of the title compound as a light yellow solid (m.p. 142 'C). T. 4-Amino-6-bromo-1,2-dimethyl-lH-benzimidazole To a solution of 19 g (70 mmol) 6-bromo-1,2-dimethyl-4-nitro-1H-benzimidazole in 250 ml methanol were added 13.7 g (84 mmol) iron(Ill) chloride and 6 g activated charcoal. The reaction mixture was heated to 80 'C and 17 ml hydrazine hydrate (95 %) were slowly added. After refluxing 3 h, the hot re action mixture was filtered through celite and the filter cake was washed with methanol and dichloro methane. The filtrate was evaporated to leave a suspension, which was treated with n-heptane. The precipitate was collected, washed with n-heptane and dried to give 13.3 g (79 %) of the title compound as a solid (m.p. 206-209 OC). U. 6-Bromo-4-(2-ethyl-6-methyl-benzylamino)-1,2-dimethyl-1H-benzimidazole To a suspension of 12 g (50 mmol) 4-amino-6-bromo-1,2-dimethyl-IH-benzimidazole and 8.8 g (52 mmol) 2-ethyl-6-methyl-benzyl chloride in 220 ml acetone were added 5.5 g (52 mmol) sodium carbon ate and 1.5 g (10 mmol) sodium iodide. After 3 h stirring at 45 'C, the reaction mixture was poured into 400 ml water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (100:3) and crystallization with n-heptane yielded 15.6 g (84 %) of the title compound as a colourless solid (m.p. 145-147 'C). V. 6-Bromo4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1 H-benzimidazole To a suspension of 0.97 g (4 mmol) 4-amino-6-bromo-1,2-dimethyl-IH-benzimidazole and 0.66 g (4.2 mmol) 2,6-dimethyl-benzyl chloride in 25 ml acetonitrile were added 0.56 g (4 mmol) potassium carbo nate and 70 mg (0.4 mmol) potassium iodide. After 1 h stirring at 65 'C, 2 ml 1N aqueous ammonia were added and the reaction mixture was evaporated. The residue was partitioned between dichloro methane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (1:1) and crystallization from ethyl acetate/n-heptane yielded 0.93 g (64 %) of the title compound as a colourless solid (m.p. 185 'C). W. 1-Benzyloxymethyl6-bromo-4-(2-ethyl-6-methyl-benzylamino)-2-methyl-1H-benzimidazole To a suspension of 6.5 g (18.8 mmol) 4-amino-l-benzyloxymethyl-6-bromo-2-methyl-1H-benzimidazole and 3.32 g (19.7 mmol) 2-ethyl-6-methyl-benzyl chloride in 120 ml acetonitrile were added 3.0 g (28.2 mmol) sodium carbonate and 0.56 g (3.75 mmol) sodium iodide. After 3 h reflux, the reaction mixture WO 2004/054984 PCT/EP2003/014069 30 was poured into 300 ml water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chro matography on silica gel using ethyl acetate:light petroleum ether (2:3) and crystallization from diisopro pyl ether yielded 6.88 g (77 %) of the title compound as a colourless solid (m.p. 117-119 'C). X. 6-Bromo-4-(2-ethyl-6-methyl-benzylamino)-l-methyl-IH-benzimidazole To a suspension of 2.0 g (8.9 mmol) 4-amino-6-bromo-1-methyl-1H-benzimidazole and 1.6 g (9.5 mmol) 2-ethyl-6-methyl-benzyl chloride in 40 ml acetonitrile were added 1.4 g (13.1 mmol) sodium car bonate and 0.3 g (2 mmol) sodium iodide. After 1 h at 70 oC, the mixture was partitioned between di chloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloro methane:methanol (100:1) yielded 2.0 g (63 %) of the title compound as a colourless solid (m.p. 132 134 °C). Y. 6-Bromo-4-(2-ethyl-6-methyl-benzylamino)-2-methoxymethyl-1-methyl-1H-benzimidazole To a suspension of 6.8 g (25.2 mmol) 4-amino-6-bromo-2-methoxymethyl-1-methyl-1H-benzimidazole and 4.46 g (26.4 mmol) 2-ethyl-6-methyl-benzylchloride in 70 ml acetonitrile were added 7.0 g (50.3 mmol) potassium carbonate and a catalytic amount of potassium iodide. After 5 h at 70 OC, the reaction mixture was poured into 200 ml water and extracted with dichloromethane. The organic layer was sepa rated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (1:1) and crystallization from diisopropyl ether yielded 5.46 g (54 %) of the title compound as a colourless solid (m.p. 110-112 0C). Z. 6-Bromo-4-(2,6-dimethyl-benzylamino)-2-methoxymethyl-l-methyl-1H-benzimidazole To a suspension of 2.5 g (9.25 mmol) 4-amino-6-bromo-2-methoxymethyl-1 -methyl-I H-benzimidazole and 1.52 g (9.72 mmol) 2,6-dimethyl-benzyl chloride in 50 ml acetonitrile were added 2.56 g (18.5 mmol) potassium carbonate and a catalytic amount of potassium iodide. After 3 h at 70 OC, the reaction mixture was poured into 150 ml water and extracted with dichloromethane. The organic layer was sepa rated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (100:1) and crystallization from diisopro pyl ether yielded 0.84 g (23 %) of the title compound as a colourless solid (m.p. 143-145 0C). AA. 4-Amino-6-(N,N-dimethylaminocarbonyl)-1,2-dimethyl-lH-benzimidazole To a suspension of 3 g (12.5 mmol) 4-amino-6-bromo-1,2-dimethyl-1H-benzimidazole in 100 ml di methylamine (2M in tetrahydrofuran) were added 280 mg (1.25 mmol) palladium(ll) acetate and 2 g (7.5 mmol) triphenylphosphine. The mixture was transferred to an autoclave and carbonylated (6 bar carbon monoxide pressure, 120 oC) for 16 h. The reaction mixture was cooled down, poured into 200 ml water and 100 ml saturated aqueous ammonium chloride and extracted with dichloromethane. The organic layer was separated, washed with water, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate/methanol (4:1) WO 2004/054984 PCT/EP2003/014069 31 and crystallization from diisopropyl ether yielded 0.7 g (24 %) of the title compound as a colourless solid (m.p. 230-234 °C). BB. Cyclopropanecarboxylic acid (2-benzyloxy-4-bromo-6-nitro-phenyl)-amide A suspension of 20.0 g (61.9 mmol) 2-benzyloxy-4-bromo-6-nitro-aniline and 11.2 ml (123.4 mmol) cyclopropanecarbonyl chloride in 130 ml dioxane was heated to 100 'C. After 5 h, the flask was im mersed in an ice bath, the precipitate was collected, washed with toluene and dried in vacuo to give 21.2 g (87 %) of the title compound as a yellow solid (m.p. 191 'C). CC. Cyclopropanecarboxylic acid (2-amino-6-benzyloxy-4-bromo-phenyl)-amide A suspension of 11.0 g (28.1 mmol) cyclopropanecarboxylic acid (2-benzyloxy-4-bromo-6-nitro-phenyl) amide, 3.0 g (18.5 mmol) iron(lll) chloride and 7.4 g activated charcoal in 140 ml methanol was heated to reflux. To the reaction mixture were added 14.7 ml hydrazine hydrate (95 %) to maintain gentle re flux. After complete reaction (1 h), the mixture was cooled down and filtered through celite. The filter cake was washed thoroughly with hot methanol/acetone and the filtrate was evaporated to dryness. The residue was crystallized from ethyl acetate to give 7.5 g (73 %) of the title compound as a colourless solid (m.p. 207-208 'C). DD. 4-Benzyloxy-6-bromo-2-cyclopropyl-i-methyl-I H-benzimidazole A suspension of 7.5 g (20.8 mmol) cyclopropanecarboxylic acid (2-amino-6-benzyloxy-4-bromo-phenyl) amide in 80 ml methanol and 13.3 ml formaldehyde (37 %) was acidified with saturated methanolic hydrogen chloride to give a clear yellow solution. To the solution were added 0.75 g (11.9 mmol) so dium cyanoborohydride in small portions. After complete reaction (4 h), the mixture was poured into water and neutralized with 40% aqueous sodium hydroxide. The precipitate was collected, washed with water and dried over phosphorus pentoxide to yield 5.3 g of a colourless solid. The solid was sus pended in 10 ml phosphoryl chloride and the mixture was heated to 90 oC for 2 h. After the reaction was complete, the mixture was diluted with dichloromethane and neutralized with with 6N aqueous potas sium hydroxide and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using tolu ene:dioxane (10:1) and crystallization from diethyl ether yielded 2.97 g (40 %) of the title compound as a colourless solid (m.p. 153-154 oC). EE. Ethyl 2-cyclopropyl-4-hydroxy-1l-methyl-IH-benzimidazole-6-carboxylate A suspension of 2.3 g (6.6 mmol) ethyl 4-benzyloxy-2-cyclopropyl-1-methyl-1 H-benzimidazole-6 carboxylate in 23 ml methanol was hydrogenated over 0.27 g 10% Pd/C (25 OC, 1 bar H 2 ) for 5 h. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from ethyl acetate to give 1.5 g (88 %) of the title compound as a colourless solid (m.p. 201-202 °C). FF. 4-Amino-N,N-dimethyl-3,5-dinitro-benzenesulfonamide A suspension of 5.0 g (27.3 mmol) 2,6-dinitroaniline in 40 ml chlorosulphonic acid was heated to 100 0C. After 2.5 h, the reaction mixture was cooled down and cautiously poured onto 1000 ml crushed ice.
WO 2004/054984 PCT/EP2003/014069 32 The suspension was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was dissolved in 100 ml tetrahydrofuran and a solution of 25 ml dimethylamine in 25 ml tetrahydrofuran was slowly added. After 20 min, the suspension was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethanol yielded 6.7 g (85 %) of the title compound as an orange solid (m.p. 169-170 oC). GG. 3,4-Diamino-N,N-dimethyl-5-nitro-benzenesulfonamide 50 ml 2N aqueous ammonia were saturated with hydrogen sulfide at 0 'C. The solution was diluted with 50 ml ethanol and 5.58 g (19.2 mmol) 4-amino-N,N-dimethyl-3,5-dinitro-benzenesulfonamide were added. After 40 min at 60 OC, the mixture was diluted with water and filtered through celite. The filter cake was extracted several times with boiling dichloromethane and methanol. The combined extracts were evaporated and the residue recrystallized from ethanol/diethyl ether to yield 1.18 g (24 %) of the title compound as a red solid (m.p. 211-213 'C). HH. 2-Methyl-7-nitro-3H-benzimidazole-5-sulfonic acid dimethylamide A suspension of 1.0 g (3.84 mmol) 3,4-diamino-N,N-dimethyl-5-nitro-benzenesulfonamide in 20 ml ethanol and 5 ml 5N hydrochloric acid was heated to 80 'C. To the reaction mixture were added 1.6 ml (15.4 mmol) 2,4-pentanedione in two portions over a period of 1 h. The solution was cooled down and neutralized with 6N aqueous sodium hydroxide. The precipitate was collected, washed with water and dried in vacuo over phosphorus pentoxide to give 0.99 g (90 %) of a beige solid (m.p. 254-255 0C). II. 2,3-Dimethyl-7-nitro-3H-benzimidazole-5-sulfonic acid dimethylamide A suspension of 1.87 g (6.6 mmol) 2-methyl-7-nitro-3H-benzimidazole-5-sulfonic acid dimethylamide, 1.82 g (13.2 mmol) potassium carbonate and 0.71 ml (11.5 mmol) methyl iodide in 50 ml acetone was stirred 3 h at ambient temperature. The mixture was partitioned between dichloromethane and satu rated aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magne sium sulphate and evaporated to dryness. Recrystallization of the residue from boiling ethyl acetate yielded 1.5 g (76 %) of the title compound as a beige solid (m.p. 194-196 0C). JJ. 7-Amino-2,3-dimethyl-3H-benzimidazole-5-sulfonic acid dimethylamide A suspension of 1.2 g (4.0 mmol) 2,3-dimethyl-7-nitro-3H-benzimidazole-5-sulfonic acid dimethylamide in 15 ml methanol and 5 ml acetic acid was heated to 60 0C and 1.1 g (20 mmol) iron filings were added. After 1.5 h, the solids were filtered off and extracted several times with boiling dichloromethane. The combined extracts were evaporated and the residue was crystallized from ethyl acetate/n-heptane to yield 0.99 g (92 %) of the title compound as a beige solid (m.p. 255-258 oC).
WO 2004/054984 PCT/EP2003/014069 33 KK. N-(4-Bromo-2,6-dinitro-phenyl)-acetamide A suspension of 5.0 g (19.1 mmol) 4-bromo-2,6-dinitroaniline in 50 ml acetic anhydride and 1 ml methanesulphonic acid was stirred 3 h at 30 'C. The precipitate was collected, washed with diethyl ether and dried to yield 4.8 g (83 %) of the title compound as a colourless solid (m.p. 238-239 'C). LL. 4-Amino-6-bromo-1l-hydroxy-2-methyl-i H-benzimidazole To a suspension of 2.0 g (6.6 mmol) N-(4-bromo-2,6-dinitro-phenyl)-acetamide and 0.4 g ruthenium on charcoal (5 %) in 80 ml ethanol were added 1.2 ml (24.7 mmol) hydrazine hydrate (95 %) over a period of 1.5 h at 60 oC. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was extracted with boiling ethyl acetate to leave 1.23 g (77 %) of the title compound as a light grey solid (m.p. 257-258 oC). MM. N-[5-Bromo-2-(2.chloro-acetylamino)-3-nitro-phenyl]-2-chloro-acetamide To a solution of 46.4 g (200 mmol) 4-bromo-2,6-dinitroaniline in 500 ml N,N-dimethylformamide and 20 ml pyridine were slowly added 80 ml (1000 mmol) chloroacetyl chloride. After 3 h, the reaction mixture was poured into 600 ml ice water and the resulting suspension was neutralized with 6N aqueous so dium hydroxide. The precipitate was collected, washed with water and dried in vacuo to yield 74.1 g (96 %) of the title compound as a beige solid (m.p. 172-173 oC). NN. 6-Bromo-2-chloromethyl-4-nitro-1lH-benzimidazole A suspension of 1.0 g (2.59 mmol) N-[5-bromo-2-(2-chloro-acetylamino)-3-nitro-phenyl]-2-chloro acetamide in 25 ml 4N hydrochloric acid and 20 ml ethanol was heated to reflux. After 4 h, the reaction mixture was poured into 75 ml water and neutralized with saturated aqueous sodium hydrogen carbon ate. The precipitate was collected, washed with water and dried over phosphorus pentoxide to give 0.65 g (86 %) of the title compound as an orange solid (m.p. 148-150 oC). OO. 6-Bromo-2-chloromethyl-1l-methyl-4-nitro-1IH-benzimidazole To a solution of 39.3 g (135.3 mmol) 6-bromo-2-chloromethyl-4-nitro-1H-benzimidazole in 500 ml ace tone were added 26.0 g (206.1 mmol) dimethyl sulphate and 50.0 g (362 mmol) potassium carbonate. After 1.25 h stirring at room temperature, the reaction mixture was poured into 1000 ml water. The pre cipitate was collected, washed with water and recrystallized from methanol to give 32.5 g (63 %) of the title compound as a beige solid (m.p. 154-155 'C). PP. 2-Acetoxymethyl-6-bromo-1l-methyl-4-nitro-1H-benzimidazole To a solution of 30.0 g (98.5 mmol) 6-bromo-2-chloromethyl-1-methyl-4-nitro-1H-benzimidazole in 200 ml acetone were added 16.4 g (98.5 mmol) potassium iodide. The resulting suspension was stirred 1 h at ambient temperature and 14.5 g (147.8 mmol) potassium acetate were added. After 2 h at 40 'C, the reaction mixture was poured into 500 ml water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated to dryness. Recrystallization of the residue from boiling ethanol yielded 23.9 g (74 %) of the title compound as an orange solid (m.p. 143-145 0C).
WO 2004/054984 PCT/EP2003/014069 34 QQ. 2-Acetoxymethyl-4-amino-6-bromo-l-methyl-1H-benzimidazole To a suspension of 10.0 g (30.5 mmol) 2-acetoxymethyl-6-bromo-1-methyl-4-nitro-1H-benzimidazole in 40 ml acetic acid were added 6.8 g (122 mmol) iron filings and the reaction mixture was heated to 60 'C. After 4 h, a further amount of 1.0 g (18 mmol) iron filings were added and heating was continued for 1.25 h. The precipitate was collected, dissolved in dichloromethane and extracted with water. The or ganic layer was separated, dried over anhydrous magnesium sulphate and evaporated to dryness. Puri fication of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (7:3) and crystallization from ethyl acetate/n-heptane yielded 4.6 g (51 %) of the title compound as a beige solid (m.p. 104-106 oC). RR. 4-Amino-6-bromo-2-hydroxymethyl-1-methyl-IH-benzimidazole A suspension of 7.5 g (22.9 mmol) 2-acetoxymethyl-6-bromo-1-methyl-4-nitro-IH-benzimidazole in 180 ml methanol was hydrogenated over Raney nickel (25 'C, 1 bar 1-12) for 2.5 h. The catalyst was filtered off and the filtrate was partitioned between water and dichloromethane. The organic layer was sepa rated, dried over anhydrous magnesium sulphate and evaporated. The residue was crystallized from ethanol/diisopropyl ether to give 1.32 g (22 %) of the title compound as a solid (m.p. 216-218 0C). SS. 2,6-Dibromo-1 -methyl-4-nitro-I H-benzimidazole To a solution of 1.0 g (3.9 mmol) 6-bromo-1-methyl-4-nitro-lH-benzimidazole in 25 ml dichloroethane were added 5 g silica gel and 0.94 g (5.3 mmol) N-bromosuccinimide. After 2.5 h at 85 °C, the mixture was cooled down and filtered. The filtrate was extracted with saturated aqueous sodium hydrogen car bonate, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by col umn chromatography on silica gel using ethyl acetate:light petroleum ether (1:1) and crystallization from ethyl acetateln-heptane yielded 0.745 g (57 %) of the title compound as a yellow solid (m.p. 235 236 0C). TT. 6-Bromo-2-(N,N-dimethylamino)--methyl-4-nitro-1 H-benzimidazole To a solution of 3.0 g (11.7 mmol) 6-bromo-1-methyl-4-nitro-1H-benzimidazole in 75 ml dichloroethane were added 25 g silica gel and 2.5 g (14.1 mmol) N-bromosuccinimide. After 3 h at 85 OC, the mixture was cooled down and filtered. The filtrate was evaporated and the residue was dissolved in 100 ml tetrahydrofuran. A solution of 10 ml dimethylamine in 20 ml tetrahydrofuran was slowly added and the mixture was stirred for 4 h. The mixture was evaporated to 114 of its volume and partitioned between saturated aqueous sodium hydrogen carbonate and dichloromethane. The organic layer was sepa rated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystal lization from ethyl acetate yielded 1.6 g (46 %) of the title compound as an orange coloured solid (m.p. 206-207 0C). UU. 4-Amino-6-bromo-2-(N,N-dimethylamino)-I -methyl-I H-benzimidazole To a suspension of 1.0 g (3.3 mmol) 6-bromo-2-(N,N-dimethylamino)-1-methyl-4-nitro-1H benzimidazole in 25 ml methanol and 8 ml acetic acid were added 0.85 g (15.2 mmol) iron powder at 65 WO 2004/054984 PCT/EP2003/014069 35 oC. After 2 h, the solids were filtered off and washed with dichloromethane. The filtrate was extracted with water, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate and crystallization from diethyl ether yielded 0.2 g (22 %) of the title compound as a colourless solid (m.p. 137 °C). W. 6-Bromo-1,2-dimethyl-4-(2-methyl-benzylamino)-1 H-benzimidazole To a solution of 0.9 ml (6.4 mmol) 2-methyl-benzyl chloride in 20 ml acetone were added 1.1 g (6.6 mmol) sodium iodide and the mixture was stirred 1.5 h at room temperature. The solid was filtered off and 1.5 g (4.4 mmol) 4-amino-6-bromo-1,2-dimethyl-1 H-benzimidazole and 1.3 g (9.4 mmol) potassium carbonate were added to the filtrate. After 3 h at reflux, the mixture was partitioned between water and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloro methane:methanol (30:1) and crystallization from ethyl acetate/n-heptane yielded 1.28 g (61 %) of the title compound as a colourless solid (m.p. 128-129 0C). WW. 6-Bromo-4-(2,4-dimethyl-furan-3-yl-methylamino)-1,2-dimethyl-1lH-benzimidazole To a suspension of 1.95 g (4.6 mmol) Dess-Martin-periodinane in 10 ml dichloromethane and 0.5 ml pyridine was dropwise added a solution of 0.5 g (4.0 mmol) (2,4-dimethyl-furan-3-yl)-methanol in 5 ml dichloromethane at room temperature. After 30 min, water and 1 ml saturated aqueous sodium sulfite were added and the mixture was extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. The residue was filtered through silica gel using ethyl acetate:light petroleum ether (9:1) to leave a colourless oil after evaporation. The crude product was dissolved in 10 ml methanol and 0.5 ml acetic acid. After addition of 0.48 g (2 mmol) 4 amino-6-bromo-1,2-dimethyl-1 H-benzimidazole, 0.3 g (4.8 mmol) sodium cyanoborohydride were added in three portions over a period of 2.5 h. After 2 h, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with dichloromethane. The organic layer was dried over an hydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate and crystallization from ethyl acetate/n-heptane yielded 0.45 g (65 %) of the title compound as a colourless solid (m.p. 207-208 0C). XX. 6-Bromo-4-(2-hydroxymethyl-6-methyl-benzylamino)-1,2-dimethyl-1lH-benzimidazole To a solution of 0.8 g (5.4 mmol) 7-methyl-3H-isobenzofuran-1-one in 15 ml dried toluene were slowly added 4.3 ml (6.5 mmol) diisobutylaluminium hydride (1.5M in toluene) at -78 0C. After 1 h, the reaction mixture was quenched with 1 ml methanol and allowed to warm to room temperature. The mixture was partitioned between saturated aqueous potassium sodium tartrate and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. The oil thus obtained was dissolved in 20 ml methanol and 1 ml acetic acid. After the addition of excess sodium cyanoboro hydride, the mixture was stirred 4 h at 45 0C. The mixture was partitioned between water and dichloro methane and neutralized with 6N aqueous sodium hydroxide. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatog- WO 2004/054984 PCT/EP2003/014069 36 raphy on silica gel using ethyl acetate and crystallization from ethyl acetate/n-heptane yielded 0.35 g (24 %) of the title compound as a colourless solid (m.p. 215-216 'C). YY. 6-Bromo-4-(2-ethyl-6-methyl-benzylamino)-2-hydroxymethyl-I-methyl-1H-benzimidazole A suspension of 1.25 g (4.88 mmol) 4-amino-6-bromo-2-hydroxymethyl-1 -methyl-1 H-benzimidazole, 0.86 g (5.12 mmol) 2-ethyl-6-methyl-benzyl chloride, 1.35 g (9.76 mmol) potassium carbonate and a catalytic amount of potassium iodide in 15 ml acetonitrile was heated to 70 0C. After 6 h, the reaction mixture was poured into water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chro matography on silica gel using dichloromethane:methanol (100:3) and crystallization from diisopropyl ether yielded 0.54 g (29 %) of the title compound as a colourless solid (m.p. 206-208 0C). ZZ. 6-Bromo-2-(N,N-dimethylamino)-4-(2,6-dimethyl-benzylamino)-1-methyl- H-benzimidazole To a solution of 0.46 g (1.7 mmol) 4-amino-6-bromo-2-(N,N-dimethylamino)-1 -methyl-1 H-benzimidazole and 0.3 g (2.2 mmol) 2,6-dimethyl-benzaldehyde in 10 ml dichloromethane and 2.5 ml acetic acid were added 0.6 g (2.8 mmol) sodium triacetoxyborohydride. After 1 h at ambient temperature, saturated aqueous sodium hydrogen carbonate was added and stirring was continued for 30 min. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate and crystallization from ethyl ace tate/n-heptane yielded 0.46 g (70 %) of the title compound as a colourless solid (m.p. 157-158 OC). AAA. 1 -Benzyloxymethyl-6-bromo4-(2,6-dimethyl-benzylamino)-2-methyl-IH-benzimidazole To a suspension of 7.6 g (22 mmol) 4-amino-l-benzyloxymethyl-6-bromo-2-methyl-1 H-benzimidazole and 3.56 g (23.0 mmol) 2,6-dimethyl-benzyl chloride in 140 ml acetonitrile were added 3.5 g (32.7 mmol) sodium carbonate and 0.66 g (4.4 mmol) sodium iodide. After 3.5 h reflux, the reaction mixture was partitioned between water and dichloromethane. The organic layer was separated, dried over an hydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (2:3) and crystallization from ethyl acetate/n-heptane yielded 6.8 g (64 %) of the title compound as a colourless solid (m.p. 147-148 oC). II.Final products of the formula I 1. Methyl 4-(2-ethyl-6-methyl-benzyloxy)-1,2-dimethyl-lH-benzimidazole-6-carboxylate To a solution of 2.0 g (9.1 mmol) methyl 4-hydroxy-1,2-dimethyl-IH-benzimidazole-6-carboxylate and 1.7 g (10.1 mmol) 2-ethyl-6-methyl-benzyl chloride in 56 ml N,N-dimethylformamide were slowly added 0.7 g (17.5 mmol) sodium hydride (60 % dispersion in mineral oil). After 1 h, a further amount of 0.3 g (1.8 mmol) 2-ethyl-6-methyl-benzyl chloride was added and the mixture was stirred for 4 h. The mixture was carefully hydrolyzed with saturated aqueous ammonium chloride and partitioned between di- WO 2004/054984 PCT/EP2003/014069 37 chloromethane and water. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from water/acetone yielded 2.7 g (84 %) of the title compound as a solid (m.p. 157 oC). 2. 4-(2-Ethyl-6-methyl-benzyloxy)-1,2-dimethyl-1 H-benzimidazole-6-carboxylic Acid To a suspension of 2.6 g (7.4 mmol) methyl 4-(2-ethyl-6-methyl-benzyloxy)-1,2-dimethyl-1lH benzimidazole-6-carboxylate in 75 ml dioxane were added 15 ml 2N aqueous sodium hydroxide. After 3 h at 80 'C, the reaction mixture was cooled down and the pH was adjusted to pH = 7 by adding 6N hydrochloric acid. After addition of 50 g silica gel, the mixture was evaporated to dryness and the resi due was purified by column chromatography on silica gel using dichloromethane:methanol (4:1) Evaporation of the solvent left a solid, which was crystallized from diethyl ether to give 2.67 g (quant.) of the title compound (crude product, contained silica gel) which was used without further purification for the next step. 3. Methyl 4-(2,6-dimethyl-benzyloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylate To a solution of 3.6 g (16.4 mmol) methyl 4-hydroxy-1,2-dimethyl-IH-benzimidazole-6-carboxylate and 2.8 g (18.1 mmol) 2,6-dimethyl-benzyl chloride in 100 ml N,N-dimethylformamide were slowly added 1.3 g (32.5 mmol) sodium hydride (60 % dispersion in mineral oil) over a period of 2 h. After complete reac tion, the mixture was carefully hydrolyzed with saturated aqueous ammonium chloride and diluted with 500 ml water. The precipitate was collected, washed thoroughly with water and dried over phosphorus pentoxide to give 4.04 g (73 %) of the title compound (m.p. 165-169 0C). 4. 4-(2,6-Dimethyl-benzyloxy)-1,2-dimethyl-1 H-benzimidazole-6-carboxylic Acid To a suspension of 3.5 g (10.3 mmol) methyl 4-(2,6-dimethyl-benzyloxy)-1,2-dimethyl-1H benzimidazole-6-carboxylate in 100 ml dioxane were added 20 ml 2N aqueous sodium hydroxide. After 2 h at 80 OC, the reaction mixture was cooled down and the pH was adjusted to pH = 7 by adding 6N hydrochloric acid. After addition of 50 g silica gel, the mixture was evaporated to dryness and the resi due was put on a column and eluted with dichloromethane:methanol (4:1). Evaporation of the solvent left a solid, which was crystallized from ethyl acetate/diethyl ether to give 2.33 g (70 %) of the title com pound (m.p. 285-286 oC). 5. 4-Benzyloxy-6-hydroxymethyl-1,2-dimethyl-1 H-benzimidazole To a suspension of 0.7 g (18.4 mmol) lithium aluminium hydride in 40 ml tetrahydrofuran was slowly added a solution of 3 g (9.7 mmol) methyl 4-benzyloxy-1,2-dimethyl-1H-benzimidazole-6-carboxylate in 10 ml tetrahydrofuran. After complete addition, the reaction mixture was carefully hydrolyzed with 0.13 ml water, 0.25 ml 6N aqueous potassium hydroxide and 0.13 ml water. Anhydrous magnesium sulphate was added and the mixture was stirred 1 h. After filtration of the suspension through celite, the filtrate was evaporated and the residue was crystallized from acetone to yield 1.99 g (74 %) of the title com pound as a colourless solid (m.p. 213-214 oC).
WO 2004/054984 PCT/EP2003/014069 38 6.4-Benzyloxy-6-methoxymethyl-1,2-dimethyl-1 H-benzimidazole To a solution of 1.5 g (5.3 mmol) 4-benzyloxy-6-hydroxymethyl-1,2-dimethyl-1 H-benzimidazole in 12 ml N,N-dimethylformamide were slowly added 0.4 g (10 mmol) sodium hydride (60 % dispersion in mineral oil) and the mixture was warmed to 50 oC. After 1 h, the reaction mixture was cooled to -10 'C and 0.4 ml (6.4 mmol) methyl iodide were added over a period of 30 min. The reaction mixture was stirred 3 h and then carefully hydrolyzed with saturated aqueous ammonium chloride. The mixture was partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magne sium sulphate and evaporated. Purification of the residue by crystallization from light petroleum ether yielded 1.25 g (80 %) of the title compound as a solid (m.p. 113 oC). 7.4-Benzyloxy-6-(N,N-dimethylaminocarbonyl)-1,2-dimethyl-1H-benzimidazole To a solution of 3.0 g (9.1 mmol) 4-benzyloxy-6-bromo-1,2-dimethyl-IH-benzimidazole in 100 ml di methylamine (3.2M in tetrahydrofuran) were added 0.3 g (1.3 mmol) palladium(ll) acetate and 1.4 g (5.3 mmol) triphenylphosphine. The mixture was transferred to an autoclave and carbonylated (6 bar carbon monoxide pressure, 120 OC) for 16 h. The reaction mixture was cooled down, evaporated and the resi due was dissolved in dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate yielded 2.3 g (78 %) of the title compound as a colourless solid (m.p. 159-160 oC). 8. 6-(N,N-Dimethylaminocarbonyl)-4-(2-ethy-6-methyl-benzyloxy)-1 ,2-dimethyl-1H-benzimidazole To a suspension of 0.35 g (1.5 mmol) 6-(N,N-dimethylaminocarbonyl)-4-hydroxy-1,2-dimethyl-1lH benzimidazole and 0.32 g (3 mmol) sodium carbonate in 5 ml acetone were added 0.5 g (3 mmol) 2 ethyl-6-methyl-benzyl chloride and the mixture was stirred 20 h at ambient temperature. The mixture was partitioned between dichloromethane and water. The organic layer was separated, dried over an hydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate yielded 0.38 g (68 %) of the title compound as a colourless solid (m.p. 161 162 -C). 9. 6-(N,N-Dimethylaminocarbonyl)-4-(2,6-dimethyl-benzyloxy)-1,2-dimethyl-1H-benzimidazole To a suspension of 1.0 g (3.08 mmol) 4-(2,6-dimethyl-benzyloxy)-1,2-dimethyl-1H-benzimidazole-6 carboxylic acid in 40 ml dichloromethane and 10 ml N,N-dimethylformamide were added 1.7 g (5.3 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate (TBTU) and the mix ture was heated to 40 C. After 1 h, 3.7 ml (18.5 mmol) of dimethylamine (5M in tetrahydrofuran) were added at ambient temperature. After 30 min, the reaction mixture was partitioned between 2N aqueous sodium hydroxide and dichloromethane. The organic layer was separated, dried over anhydrous mag nesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (13:1) gave an oil which was crystallized from ethyl acetate/light petro leum ether to yield 1.0 g (91 %) of the title compound as a yellow solid (m.p. 180 0C).
WO 2004/054984 PCT/EP2003/014069 39 10. 4-(trans-2,3-Dihydro-2-hydroxy-1-indenyloxy)-6-(N,N-dimethylaminocarbonyl)-1i,2-dimethyl 1 H-benzimidazole Oxalate To a suspension of 0.5 g (2.1 mmol) 6-(N,N-dimethylaminocarbonyl)-4-hydroxy-1,2-dimethyl-lH benzimidazole and 1.1 g (8.3 mmol) 1,2-epoxyindane in 5.3 ml methanol and 1.3 ml water were added 0.6 ml triethylamine and the mixture was heated to 70 'C for 30 min. The cooled solution was parti tioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (13:1) gave an oil which was dissolved in acetone and treated with a solution of 0.27 g (2.1 mmol) oxalic acid dihydrate in acetone. The precipitate was collected and washed with acetone to yield 0.64 g (65 %) of the title compound as a colourless solid (m.p. 144-145 °C). 11. 4-[(18,2S)-2,3-Dihydro-2-hydroxy-1-indenyloxy]-6-(N,N-dimethylaminocarbonyl)-1,2-dimethyl 1IH-benzimidazole Oxalate To a suspension of 0.5 g (2.1 mmol) 6-(N,N-dimethylaminocarbonyl)-4-hydroxy-1,2-dimethyl-IH benzimidazole and 0.75 g (5.7 mmol) (1R,2S)-epoxyindane in 5 ml ethanol and 1.25 ml water were added 0.6 ml triethylamine and the mixture was heated to 60 °C for 48 h. The cooled solution was parti tioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (13:1) gave an oil which was dissolved in acetone and treated with a solution of 0.12 g (1 mmol) oxalic acid dihydrate in acetone. The precipitate was collected and washed with acetone and diethylether to yield 0.14 g (14 %) of the title compound as a colourless solid (m.p. 126-127 0C, 92 % ee). 12. 4-(trans-2,3-Dihydro-2-methoxy-1-indenyloxy)-6-(N,N-dimethylaminocarbonyl)-1,2-dimethyl 1 H-benzimidazole Oxalate To a solution of 0.57 g (1.56 mmol) 4-(trans-2,3-dihydro-2-hydroxy-1-indenyloxy)-6-(N,N dimethylaminocarbonyl)-1,2-dimethyl-1 H-benzimidazole in 5 ml N,N-dimethylformamide were slowly added 0.15 g (2.3 mmol) sodium hydride (60 % dispersion in mineral oil) at 0 'C. After 5 min, 0.13 ml (2 mmol) methyl iodide were added and stirring was continued for 40 min at ambient temperature. The reaction mixture was carefully hydrolyzed with 1 ml 1N aqueous ammonia and partitioned between di chloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using tolu ene:dioxane:methanol (6:3:1) gave an oil which was dissolved in acetone and treated with a solution of 0.19 g (1.6 mmol) oxalic acid dihydrate in acetone. The precipitate was collected and washed with ace tone and diethyl ether to yield 0.51 g (70 %) of the title compound as a colourless solid (m.p. 126-127
OC).
WO 2004/054984 PCT/EP2003/014069 40 13.4-[trans-2,3-Dihydro-2-(methoxymethylcarbonyloxy)-1-indenyloxy]-6-(N,N-dimethylamino carbonyl)-1,2-dimethyl-1 H-benzimidazole To a solution of 0.2 ml (1.9 mmol) methoxyacetic acic in 4 ml tetrahydrofuran were added 0.3 g (1.9 mmol) N,N'-carbonyldiimidazole. After 15 min, 0.4 g (1.1 mmol) 4-(trans-2,3-dihydro-2-hydroxy-1 indenyloxy)-6-(N,N-dimethylaminocarbonyl)-1,2-dimethyl-1lH-benzimidazole and 0.3 ml (2 mmol) 1,8 diazabicyclo[5.4.0]undec-7-ene were added and stirring was continued for 1 h. The mixture was parti tioned between dichloromethane and saturated aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using toluene:dioxane:methanol (6:3.5:0.5) and crystallization from 2-propanol/diethyl ether/n-heptane yielded 0.47 g (97 %) of the title compound as a solid (m.p. 140 0 C). 14. 4-(trans-2,3-Dihydro-2-hydroxy-1 -indenyloxy)-6-methoxymethyl-1,2-dimethyl-1lH-benz imidazole Oxalate To a suspension of 0.8 g (3.9 mmol) 4-hydroxy-6-methoxymethyl-1,2-dimethyl-1 H-benzimidazole and 1.03 g (7.8 mmol) 1,2-epoxyindane in 9.5 ml methanol and 2.5 ml water were added 1.08 ml triethyl amine and the mixture was heated to 50 oC for 4 h. The cooled solution was partitioned between di chloromethane and saturated aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatog raphy on silica gel using dichloromethane:methanol (20:1) gave an oil which was dissolved in acetone and treated with a solution of 0.51 g (4 mmol) oxalic acid dihydrate in acetone. The precipitate was collected and washed with acetone to yield 0.72 g (42 %) of the title compound as a colourless solid (purity: 93 %). 15. Ethyl 4.(trans-2,3-dihydro-2-hydroxy-1l-indenyloxy)-1,2-dimethyl-1lH-benzimidazole-6 carboxylate To a suspension of 5.0 g (21.4 mmol) ethyl 4-hydroxy-1,2-dimethyl-1lH-benzimidazole-6-carboxylate and 5.65 g (42.8 mmol) 1,2-epoxyindane in 48 ml ethanol and 12 ml water were added 6 ml triethyl amine and the mixture was heated to 60 oC for 4 h. The cooled solution was partitioned between di chloromethane and saturated aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethanol/diethyl ether yielded 5.66 g (72 %) of the title compound which was used without further purifi cation in the next step. 16. 4-(trans-2,3-Dihydro-2-hydroxy-1-indenyloxy)-1 ,2-dimethyl-1H-benzimidazole-6-carboxylic Acid To a suspension of 5.6 g (15.3 mmol) ethyl 4-(trans-2,3-dihydro-2-hydroxy-1 -indenyloxy)-1,2-dimethyl 1H-benzimidazole-6-carboxylate in 50 ml dioxane were added 10 ml 2N aqueous sodium hydroxide. After 2.5 h at 80 'C, the reaction mixture was cooled down and the pH was adjusted to pH = 6 by adding 6N hydrochloric acid. After addition of 50 g silica gel, the mixture was evaporated to dryness and WO 2004/054984 PCT/EP2003/014069 41 the residue was put on a column and eluted with dichloromethane:methanol (4:1). Evaporation of the solvent left a solid, which was crystallized from ethyl acetate/n-heptane to give 5.3 g (quant.) of the title compound (m.p. 306 oC). 17. Ethyl 4-(trans-5-chloro-2,3-dihydro-2-hydroxy-1l-indenyloxy)-1,2-dimethyl-1IH-benzimidazole 6-carboxylate To a suspension of 1.17 g (5.0 mmol) ethyl 4-hydroxy-1,2-dimethyl-1H-benzimidazole-6-carboxylate and 2.47 g (10 mmol) 2-bromo-5-chloro-2,3-dihydro-IH-inden-1-ol in 20 ml ethanol and 5 ml water were added 4.14 g (30 mmol) potassium carbonate and the mixture was heated to 50 oC. After 2 h, a further amount of 1 g (4 mmol) 2-bromo-5-chloro-2,3-dihydro-lH-inden-1-ol and 2 g (14.5 mmol) potassium carbonate were added and stirring was continued for 5 h. The cooled solution was partitioned between dichloromethane and saturated aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatog raphy on silica gel using dichloromethane:methanol (100:3) yielded 0.52 g (26 %) of the title compound which was used without further purification in the next step. 18. 4-(trans-5-Chloro-2,3-dihydro-2-hydroxy-1 -indenyloxy)-1,2-dimethyl-1 H-benzimidazole-6 carboxylic Acid To a suspension of 0.51 g (1.27 mmol) ethyl 4-(trans-5-chloro-2,3-dihydro-2-hydroxy-1-indenyloxy)-1,2 dimethyl-IH-benzimidazole-6-carboxylate in 13 ml dioxane were added 2.5 ml 2N aqueous sodium hydroxide. After 4 h at 80 oC, the reaction mixture was cooled down and the pH was adjusted to pH = 6 by adding 6N hydrochloric acid. After addition of 50 g silica gel, the mixture was evaporated to dryness and the residue was put on a column and eluted with dichloromethane:methanol (4:1). Evaporation of the solvent left a solid, which was crystallized from n-heptane to give 0.63 g of the title compound (con tained silica gel), which was used without further purification in the next step. 19. 4-(trans-5-Chloro-2,3-dihydro-2-hydroxy-1-indenyloxy)-6-(N,N-dimethylaminocarbonyl)-1,2 dimethyl-IH-benzimidazole Oxalate To a suspension of 0.63 g ('1.27 mmol', contained silica gel) 4-(trans-5-chloro-2,3-dihydro-2-hydroxy-1 indenyloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid in 14 ml dichloromethane and 7 ml N,N dimethylformamide were added 0.6 g (1.9 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyl uronium tetrafluoroborate (TBTU) and the mixture was heated to 40 'C. After 30 min, 1.5 ml (7.5 mmol) dimethylamine (5M in tetrahydrofuran) were added at ambient temperature. After 30 min, the reaction mixture was partitioned between 2N aqueous sodium hydroxide and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel using dichloromethane:methanol (13:1). The product fractions were evaporated and the residue was dissolved in acetone and treated with a solution of 0.27 g (2.1 mmol) oxalic acid dihydrate in acetone. After cooling, the precipitate was collected and washed with acetone to yield 0.42 g of the title compound as a colourless solid (m.p. 158-159 0C).
WO 2004/054984 PCT/EP2003/014069 42 20. Ethyl 4-(trans-2,3-dihydro-2-hydroxy-4,7-dimethyl-1-indenyloxy)-1,2-dimethyl-1 H-benzimi dazole-6-carboxylate To a suspension of 1.17 g (5.0 rnmol) ethyl 4-hydroxy-1,2-dimethyl-lH-benzimidazole-6-carboxylate and 2.41 g (10 mmol) 2-bromo-2,3-dihydro-4,7-dimethyl-1H-inden-1-ol in 20 ml ethanol and 5 ml water were added 4.14 g (30 mmol) potassium carbonate and the mixture was heated to 50 OC. After 1 h, a further amount of 2.41 g (10 mmol) 2-bromo-2,3-dihydro-4,7-dimethyl-lH-inden-1-ol and 1.4 g (10 mmol) potassium carbonate were added and stirring was continued 1 h. The cooled solution was parti tioned between dichloromethane and saturated aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (100:3) and crystallization from ethyl acetate/n-heptane yielded 0.85 g (43 %) of the title compound as a colourless solid (m.p. 184 0C). 21. 4-(trans-2,3-Dihydro-2-hydroxy-4,7-dimethyl-1-indenyloxy)-1,2-dimethyl-1H-benzimidazole-6 carboxylic Acid To a suspension of 0.8 g (2 mmol) ethyl 4-(trans-2,3-dihydro-2-hydroxy-4,7-dimethyl-1-indenyloxy)-1,2 dimethyl-lH-benzimidazole-6-carboxylate in 20 ml dioxane were added 4 ml 2N aqueous sodium hy droxide. After 4 h at 80 0C, the reaction mixture was cooled down and the pH was adjusted to pH = 6 by adding 10% hydrochloric acid. After addition of 50 g silica gel, the mixture was evaporated to dryness and the residue was put on a column and eluted with dichloromethane:methanol (4:1). Evaporation of the solvent left 0.8 g of the title compound (contained silica gel) as a solid, which was used without fur ther purification in the next step. 22.4-(trans-2,3-Dihydro-2-hydroxy-4,7-dimethyl-1-indenyloxy)-6-(N,N-dimethylaminocarbonyl) 1,2-dimethyl-1H-benzimidazole To a suspension of 0.7 g ('1.8 mmol', contained silica gel) 4-(trans-2,3-dihydro-2-hydroxy-4,7-dimethyl 1-indenyloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid in 20 ml dichloromethane and 10 ml N,N-dimethylformamide were added 0.8 g (2.5 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyl uronium tetrafluoroborate (TBTU) and the mixture was heated to 40 oC. After 30 min, 2 ml (10 mmol) dimethylamine (SM in tetrahydrofuran) were added at ambient temperature. After 20 min, the reaction mixture was partitioned between 2N aqueous sodium hydroxide and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel using dichloromethane:methanol (13:1). Crystallization from ethyl acetate/n-heptane yielded 0.72 g of the title compound as a colourless solid (m.p. 134 0C). 23.4-(trans-2,3-Dihydro-2-hydroxy-1l-indenyloxy)-1,2-dimethyl-6-[(1-pyrrolidino)carbonyl]-I H benzimidazole Oxalate To a suspension of 1.0 g (2.96 mmol) 4-(trans-2,3-dihydro-2-hydroxy-1 -indenyloxy)-1,2-dimethyl-1 H benzimidazole-6-carboxylic acid in 20 ml dichloromethane and 10 ml 1-methyl-2-pyrrolidinone were added 1.45 g (4.5 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate (TBTU) and the mixture was heated to 40 'C. After 15 min, 0.49 ml (6 mmol) pyrrolidine were added at WO 2004/054984 PCT/EP2003/014069 43 ambient temperature. After 2 h, the reaction mixture was partitioned between saturated aqueous am monium chloride and dichloromethane. The organic layer was separated, dried over anhydrous magne sium sulphate and evaporated. The residue was purified by column chromatography on silica gel using dichloromethane:methanol (13:1). The oil thus obtained was dissolved in acetone and treated with a solution of 0.38 g (3 mmol) oxalic acid dihydrate in acetone. The precipitate was collected and washed with acetone and diethyl ether to yield 1.06 g (74 %) of the title compound as a colourless solid (m.p. 124 oC). 24.4-(trans-2,3-Dihydro-2-hydroxy-1-indenyloxy)-6-[N-(2-methoxyethyl)-N-methyl-amino carbonyl]-1,2-dimethyl-1H-benzimidazole Oxalate To a suspension of 1.0 g (2.96 mmol) 4-(trans-2,3-dihydro-2-hydroxy-1 -indenyloxy)-1,2-dimethyl-1 H benzimidazole-6-carboxylic acid in 20 ml dichloromethane and 10 ml 1-methyl-2-pyrrolidinone were added 1.45 g (4.5 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate (TBTU) and the mixture was heated to 40 oC. After 15 min, 0.54 g (6 mmol) N-(2-methoxyethyl)-N methyl-amine were added at ambient temperature. After 1 h, the reaction mixture was partitioned be tween saturated aqueous ammonium chloride and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by column chro matography on silica gel using dichloromethane:methanol (13:1). The product fractions were evapo rated and the residue was dissolved in acetone and treated with a solution of 0.19 g (1.5 mmol) oxalic acid dihydrate in acetone. The precipitate was collected and washed with acetone and diethyl ether to yield 0.55 g (38 %) of the title compound as a colourless solid (m.p. 141 'C). 25. 4-(trans-2,3-Dihydro-2-hydroxy-1-indenyloxy)-1 ,2-dimethyl-6-[(1-piperidino)carbonyl]-1H benzimidazole Oxalate To a suspension of 1.3 g (3.84 mmol) 4-(trans-2,3-dihydro-2-hydroxy-1-indenyloxy)-1,2-dimethyl-lH benzimidazole-6-carboxylic acid in 25 ml dichloromethane and 10 ml N,N-dimethylformamide were added 1.85 g (5.76 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate (TBTU) and the mixture was heated to 40 OC. After 15 min, 0.64 ml (7.7 mmol) piperidine were added at ambient temperature. After 1 h, the reaction mixture was partitioned between saturated aqueous ammonium chloride and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel using dichloromethane:methanol (13:1). The oil thus obtained was dissolved in acetone and treated with a solution of 0.25 g (2 mmol) oxalic acid dihydrate in acetone. The precipitate was collected and washed with acetone and diethyl ether to yield 0.95 g (50 %) of the title compound as a colourless solid (m.p. 115-116 'C). 26.6-(Cyclopropylaminocarbonyl)-4-(trans-2,3-dihydro-2-hydroxy-1-indenyloxy)-1,2-dimethyl-1H benzimidazole To a suspension of 1.0 g (2.96 mmol) 4-(trans-2,3-dihydro-2-hydroxy-1 -indenyloxy)-1,2-dimethyl-1 H benzimidazole-6-carboxylic acid in 20 ml dichloromethane and 10 ml N,N-dimethylformamide were added 1.45 g (4.5 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate WO 2004/054984 PCT/EP2003/014069 44 (TBTU) and the mixture was heated to 40 'C. After I h, 0.45 ml (6.5 mmol) cyclopropylamine were added at ambient temperature. After 1 h, the reaction mixture was partitioned between 2N aqueous sodium hydroxide and dichloromethane. The organic layer was separated, dried over anhydrous mag nesium sulphate and evaporated. The residue was purified by crystallization from ethyl ace tate/methanol/n-heptane to yield 0.78 g (70 %) of the title compound as a colourless solid (m.p. 148 149 -C). 27. Ethyl 4-(2-ethyl-6-methyl-benzylamino)-1,2-dimethyl-1H-benzimidazole-6-carboxylate 1.0 g (2.7 mmol) 6-bromo-4-(2-ethyl-6-methyl-benzylamino)-1,2-dimethyl-1 H-benzimidazole were dis solved in 15 ml ethanol and 2.5 ml triethylamine and transferred to an autoclave. After addition of 0.1 g (0.45 mmol) palladium(ll) acetate and 0.33 g (1.25 mmol) triphenylphosphine, the reaction mixture was carbonylated (5 bar carbon monoxide pressure, 100 'C) for 16 h. The reaction mixture was cooled down, filtered and evaporated to leave an orange coloured oil which was dissolved in ethyl acetate and extracted with water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetatellight petroleum ether yielded 0.8 g (81 %) of the title compound as a colourless solid (m.p. 171-173 'C). 28. Ethyl 4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1 H-benzimidazole-6-carboxylate 8.8 g (24.6 mmol) 6-bromo-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1 H-benzimidazole were dis solved in 130 ml ethanol and 21.3 ml triethylamine and transferred to an autoclave. After addition of 0.8 g (3.6 mmol) palladium(ll) acetate and 3.2 g (12.2 mmol) triphenylphosphine, the reaction mixture was carbonylated (10 bar carbon monoxide pressure, 100 0C) for 16 h. The reaction mixture was cooled down, filtered and evaporated to leave an orange coloured oil which was dissolved in dichioromethane and extracted with water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl ace tate:light petroleum ether (1:1) and crystallization from ethyl acetate yielded 6.18 g (72 %) of the title compound as a colourless solid (m.p. 190 0C). 29. Ethyl 4-(2-ethyl-6-methyl-benzylamino)-2-methoxymethyl-1-methyl-1H-benzimidazole-6 carboxylate 3.4 g (8.45 mmol) 6-bromo-4-(2-ethyl-6-methyl-benzylamino)-2-methoxymethyl-1 -methyl-i H benzimidazole were dissolved in 80 ml ethanol and 10 ml triethylamine and transferred to an autoclave. After addition of 0.28 g (1.3 mmol) palladium(ll) acetate and 1.1 g (4.2 mmol) triphenylphosphine, the reaction mixture was carbonylated (6 bar carbon monoxide pressure, 100 0C) for 16 h. The reaction mixture was cooled down, poured into 250 ml water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (3:7) and crys tallization from diisopropyl ether yielded 2.2 g (66 %) of the title compound as a colourless solid (m.p. 106-107 oC).
WO 2004/054984 PCT/EP2003/014069 45 30. Ethyl 4-(2,6-dimethyl-benzylamino)-2-methoxymethyl-I-methyl-I H-benzimidazole-6 carboxylate 2.5 g (6.43 mmol) 6-bromo-4-(2,6-dimethyl-benzylamino)-2-methoxymethyl-1 -methyl-1 H-benzimidazole were dissolved in 60 ml ethanol and 7 ml triethylamine and transferred to an autoclave. After addition of 0.22 g (0.96 mmol) palladium(ll) acetate and 0.84 g (3.2 mmol) triphenylphosphine, the reaction mixture was carbonylated (6 bar carbon monoxide pressure, 110 oC) for 16 h. The reaction mixture was cooled down, poured into 250 ml water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chro matography on silica gel using ethyl acetate:light petroleum ether (1:1) and crystallization from diisopro pyl ether yielded 1.84 g (81 %) of the title compound as a yellow solid (m.p. 134-135 'C). 31. 4-(2-Ethyl-6-methyl-benzylamino)-1,2-dimethyl-IH-benzimidazole-6-carboxylic Acid To a suspension of 5.0 g (13.7 mmol) ethyl 4-(2-ethyl-6-methyl-benzylamino)-1,2-dimethyl-1H benzimidazole-6-carboxylate in 80 ml dioxane were added 50 ml 2N aqueous sodium hydroxide. After 2 h at 100 0C, the reaction mixture was cooled down, poured into 50 ml saturated aqueous ammonium chloride and the pH was adjusted to pH = 6 by adding 6N hydrochloric acid. The thick precipitate was collected, washed with water and recrystallized from ethanol to give 3.7 g (81 %) of the title compound as a colourless solid (m.p. 312-314 oC). 32. 4-(2,6-Dimethyl-benzylamino)-1,2-dimethyl-1lH-benzimidazole-6-carboxylic Acid To a suspension of 5.0 g (14.2 mmol) ethyl 4-(2,6-dimethyl-benzylamino)-l,2-dimethyl-lH benzimidazole-6-carboxylate in 50 ml dioxane were added 20 ml 2N aqueous sodium hydroxide. After 16 h at 100 0C, the reaction mixture was cooled down and the pH was adjusted to pH = 7 by adding 6N hydrochloric acid. After addition of 50 g silica gel, the mixture was evaporated to dryness and the resi due was put on a column and eluted with dichloromethane:methanol (13:1). Evaporation of the solvent left a solid, which was crystallized from acetone to give 4.15 g (90 %) of the title compound (m.p. 315 318 oC). 33. 4-(2-Ethyl-6-methyl-benzylamino)-2-methoxymethyl-l-methyl-IH-benzimidazole-6-carboxylic Acid To a suspension of 1.6 g (4.04 mmol) ethyl 4-(2-ethyl-6-methyl-benzylamino)-2-methoxymethyl-1 methyl-1 H-benzimidazole-6-carboxylate in 30 ml dioxane were added 16 ml 2N aqueous sodium hy droxide. After 2 h at 100 0C, the reaction mixture was cooled down, poured into 30 ml water and the pH was adjusted to pH = 6 by adding 6N hydrochloric acid. The precipitate was collected, washed with water and ethanol and dried over phosphorus pentoxide to give 1.06 g (71 %) of the title compound as a colourless solid (m.p. 275-278 0C).
WO 2004/054984 PCT/EP2003/014069 46 34. 4-(2,6-Dimethyl-befnzylamino)-2-methoxymethyl-1-methyl-1H-benzimidazole-6-carboxylic Acid To a suspension of 1.3 g (3.4 mmol) ethyl 4-(2,6-dimethyl-benzylamino)-2-methoxymethyl-1l-methyl-IH benzimidazole-6-carboxylate in 25 ml dioxane were added 13 ml 2N aqueous sodium hydroxide. After 3 h at 100 oC, the reaction mixture was cooled down, poured into 75 ml water and the pH was adjusted to pH = 6 by adding 6N hydrochloric acid. The precipitate was collected, washed with water, ethanol and diisopropyl ether to give 0.96 g (80 %) of the title compound as a colourless solid (m.p. 269-272 OC). 35. 4-(2-Ethyl-6-methyl-benzylamino)-6-(2-hydroxyethyl-aminocarbonyl)-1,2-dimethyl-1H benzimidazole A suspension of 1.0 g (2.74 mmol) ethyl 4-(2-ethyl-6-methyl-benzylamino)-1,2-dimethyl-IH benzimidazole-6-carboxylate in 10 ml 2-aminoethanol was heated to 110 oC for 30 h. The reaction mix ture was cooled down, diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate/diethyl ether yielded 0.72 g (69 %) of the title compound as a colourless solid (m.p. 200-201 0C). 36. 4-(2,6-Dimethyl-benzy[amino)-6-(2-hydroxyethyl-aminocarbonyl)-1,2-dimethyl-1H-benzimi dazole A suspension of 1.0 g (2.85 mmol) ethyl 4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1H-benzimidazole 6-carboxylate in 15 ml 2-aminoethanol was heated to 100 0C for 16 h. The reaction mixture was cooled down, diluted with water and extracted with dichloromethane/methanol. The organic layer was sepa rated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystal lization from ethyl acetate/methanol and activated charcoal yielded 0.64 g (61 %) of the title compound as a colourless solid (m.p. 259-260 oC). 37. 4-(2,6-Dimethyl-benzylamino)-6-(2-hydroxyethyl-aminocarbonyl)-2-methoxymethyl-1-methyl I1H-benzimidazole A suspension of 0.4 g (1.04 mmol) ethyl 4-(2,6-dimethyl-benzylamino)-2-methoxymethyl-1l-methyl-IH benzimidazole-6-carboxylate in 4 ml 2-aminoethanol was heated to 140 oC for 3 h. The reaction mixture was cooled down, poured into 15 ml water and 10 ml saturated aqueous ammonium chloride and ex tracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sul phate and evaporated. Purification of the residue by column chromatography on silica gel using tolu ene:dioxane:methanol (6:3.6:0.4) and crystallization from diisopropyl ether yielded 0.38 g (93 %) of the title compound as a colourless solid (m.p. 186-187 0C). 38. 4-(2-Ethyl-6-methyl-benzylamino)-1,2-dimethyl-1 H-benzimidazole-6-carboxamide To a suspension of 1.0 g (2.96 mmol) 4-(2-ethyl-6-methyl-benzylamino)-1,2-dimethyl-IH benzimidazole-6-carboxylic acid in 10 ml tetrahydrofuran and 5 ml N,N-dimethylformamide were added 0.54 g (3.26 mmol) N,N'-carbonyldiimidazole. After 1 h, 10 ml saturated methanolic ammonia were WO 2004/054984 PCT/EP2003/014069 47 added and stirring was continued for I h. 25 ml saturated aqueous ammonium chloride and 50 ml water were added and the mixture was extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chro matography on silica gel using toluene:dioxane:methanol (6:3.8:0.2) and crystallization from ethyl ace tate/n-heptane yielded 0.8 g (80 %) of the title compound as a colourless solid (m.p. 240-241 oC). 39. 4-(2,6-Dimethyl-benzylamino)-l,2-dimethyl-IH-benzimidazole-6-carboxamide To a suspension of 1.2 g (3.7 mmol) 4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1lH-benzimidazole-6 carboxylic acid in 10 ml tetrahydrofuran and 5 ml N,N-dimethylformamide were added 0.7 g (4.3 mmol) N,N'-carbonyldiimidazole. After 1 h, ammonia gas was bubbled through the flask for 1 h. The mixture was then partitioned between dichloromethane and 2N aqueous sodium hydroxide. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate yielded 0.4 g (34 %) of the title compound as a colourless solid (m.p. 272 0C). 40. 4-(2-Ethyl-6-methyl-benzylamino)-1,2-dimethyl-6-(pyrrolidinocarbonyl)-1 H-benzimidazole To a suspension of 1.0 g (2.96 mmol) 4-(2-ethyl-6-methyl-benzylamino)-1,2-dimethyl-1H-benzimida zole-6-carboxylic acid in 10 ml tetrahydrofuran and 3 ml N,N-dimethylformamide were added 0.54 g (3.26 mmol) N,N'-carbonyldiimidazole. After 2 h, 0.63 g (3.26 mmol) pyrrolidine were added and stirring was continued. After 1 h, 20 ml saturated aqueous ammonium chloride and 50 ml water were added and the mixture was extracted with dichloromethane. The organic layer was separated, dried over an hydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using toluene:dioxane:methanol (6:3.9:0.1) and crystallization from ethyl acetate/n-heptane yielded 0.91 g (79 %) of the title compound as a solid (m.p. 126 oC). 41. 4-(2-Ethyl-6-methyl-benzylamino)-1,2-dimethyl-6-(morpholinocarbonyl)-1IH-benzimidazole To a suspension of 1.5 g (4.44 mmol) 4-(2-ethyl-6-methyl-benzylamino)-1,2-dimethyl-1H-benzimida zole-6-carboxylic acid in 20 ml tetrahydrofuran and 5 ml N,N-dimethylformamide were added 1.48 g (8.88 mmol) N,N'-carbonyldiimidazole and the mixture was heated to 60 oC. After 1 h, 1.94 g (22.2 mmol) morpholine were added and the reaction mixture was refluxed for 1 h. The mixture was then poured into 100 ml water and 20 ml saturated aqueous sodium hydrogen carbonate and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using tolu ene:dioxane:methanol (6:3.9:0.1) and crystallization from diisopropyl ether/n-heptane yielded 1.6 g (89 %) of the title compound as a colourless solid (m.p. 229-231 oC). 42. 6-(N,N-Dimethylaminocarbonyl)-4-(2-ethyl-6-methyl-benzylamino)-2-methoxymethyl-1 methyl-IH-benzimidazole To a suspension of 0.9 g (2.44 mmol) 4-(2-ethyl-6-methyl-benzylamino)-2-methoxymethyl-1-methyl-lH benzimidazole-6-carboxylic acid in 10 ml tetrahydrofuran and 3 ml N,N-dimethylformamide were added 0.8 g (4.9 mmol) N,N'-carbonyldiimidazole. After I h, 5 ml (5 mmol) dimethylamine (5M in tetrahydrofu- WO 2004/054984 PCT/EP2003/014069 48 ran) were added and stirring was continued for 4 h. The mixture was poured into 60 ml water and ex tracted with dichloromethane. The organic layer was separated, washed with water, dried over anhy drous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using toluene:dioxane:methanol (6:3.9:0.1) and crystallization from diisopropyl ether yielded 0.88 g (91 %) of the title compound as a colourless solid (m.p. 154 oC). 43. 6-(N,N-Dimethylaminocarbonyl)-4-(2,6-dimethyl-benzylamino)-2-methoxymethyl-1i-methyl-1IH benzimidazole To a suspension of 0.5 g (1.4 mmol) 4-(2,6-dimethyl-benzylamino)-2-methoxymethyl-1l-methyl-IH benzimidazole-6-carboxylic acid in 8 ml tetrahydrofuran and 3 ml N,N-dimethylformamide were added 0.46 g (2.8 mmol) N,N'-carbonyldiimidazole and the mixture was heated to 60 'C for 5 min. After 1 h at ambient temperature, 3 ml (15 mmol) dimethylamine (5M in tetrahydrofuran) were added and stirring was continued for 1 h. The mixture was poured into 40 ml water and extracted with dichloromethane. The organic layer was separated, washed with water, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using tolu ene:dioxane:methanol (6:3.8:0.2) and crystallization from diisopropyl ether yielded 0.49 g (92 %) of the title compound as a colourless solid (m.p. 156-157 'C). 44. 6-(N,N-Dimethylaminocarbonyl)-4-(2-ethyl-6-methyl-benzylamino)-1,2-dimethyl-I H benzimidazole To a solution of 9.5 g (25.5 mmol) 6-bromo-4-(2-ethyl-6-methyl-benzylamino)-1,2-dimethyl-lH benzimidazole in 225 ml dimethylamine (3.2M in tetrahydrofuran) were added 0.85 g (2.55 mmol) palla dium(ll) acetate and 4 g (15.3 mmol) triphenylphosphine. The mixture was transferred to an autoclave and carbonylated (6 bar carbon monoxide pressure, 120 oC) for 16 h. The reaction mixture was cooled down, poured into 400 ml water and extracted with dichloromethane. The organic layer was separated, washed with water, dried over anhydrous magnesium sulphate and evaporated. Purification of the resi due by column chromatography on silica gel using dichloromethane:methanol (100:3) and crystallization from boiling ethyl acetate yielded 5.8 g (76 %) of the title compound as a colourless solid (m.p. 152-153 OC). 45. 6-(N,N-Dimethylaminocarbonyl)-4-(2-ethyl-6-methyl-benzy[amino)-1-methyl-1H-benzimidazole Hydrochloride To a solution of 2.0 g (5.6 mmol) 6-bromo-4-(2-ethyl-6-methyl-benzylamino)-1 -methyl-1 H benzimidazole in 30 ml dimethylamine (5M in tetrahydrofuran) were added 0.2 g (0.9 mmol) palla dium(ll) acetate and 0.7 g (2.7 mmol) triphenylphosphine. The mixture was transferred to an autoclave and carbonylated (6 bar carbon monoxide pressure, 110 'C) for 16 h. The reaction mixture was cooled down, diluted with water and extracted with dichloromethane. The organic layer was separated, washed with water, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue was achieved by column chromatography on silica gel using first dichloromethane:methanol (13:1), then ethyl acetate. The product fractions were evaporated and treated with saturated hydrogen chloride in diethyl ether to give 0.3 g (14 %) of the title compound as a colourless solid (m.p. 183-184°C).
WO 2004/054984 PCT/EP2003/014069 49 46. 6-(N,N-Dimethylaminocarbonyl)-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1 H-benzimidazole To a solution of 0.86 g (2.4 mmol) 6-bromo-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1H benzimidazole in 30 ml dimethylamine (5M in tetrahydrofuran) were added 80 mg (0.36 mmol) palla dium(ll) acetate and 250 mg (0.96 mmol) triphenylphosphine. The mixture was transferred to an auto clave and carbonylated (5.5 bar carbon monoxide pressure, 110 °C) for 16 h. The reaction mixture was cooled down, evaporated and partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (20:1) and crystallization from ethyl acetate/n-heptane yielded 0.4 g (48 %) of the title compound as a colourless solid (m.p. 142-143 °C). 47. 6-(I-Azetidinocarbonyl)-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1H-benzimidazole To a suspension of 1.1 g (3.4 mmol) 4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1H-benzimidazole-6 carboxylic acid in 20 ml dichloromethane and 5 ml N,N-dimethylformamide were added 1.2 g (3.74 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate (TBTU) and the mix ture was heated to 40 'C. After 1 h, a solution of 0.36 g (3.74 mmol) azetidine hydrochloride in 1.14 g (11.2 mmol) triethylamine was added. After 45 min, the reaction mixture was poured into 120 ml water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magne sium sulphate and evaporated. The residue was purified by column chromatography on silica gel using toluene:dioxane:methanol (6:3.6:0.4). Crystallization from diisopropyl ether yielded 0.46 g (37 %) of the title compound as a colourless solid (m.p. 193-195 0C). 48. 1 -Benzyloxymethyl-6-(N,N-dimethylaminocarbonyl)-4-(2-ethyl-6-methyl-benzylamino)-2 methyl-lH-benzimidazole Oxalate To a solution of 6.5 g (13.6 mmol) 1-benzyloxymethyl-6-bromo-4-(2-ethyl-6-methyl-benzylamino)-2 methyl-lH-benzimidazole in 44 ml dimethylamine (SM in tetrahydrofuran) were added 0.3 g (1.36 mmol) palladium(ll) acetate and 2.1 g (8.1 mmol) triphenylphosphine. The mixture was transferred to an auto clave and carbonylated (6 bar carbon monoxide pressure, 100 'C) for 16 h. The reaction mixture was cooled down, poured into 200 ml water and extracted with ethyl acetate. The organic layer was sepa rated, washed with water, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (1:1) gave 3.1 g of a yellow oil, which was dissolved in 20 ml acetonitrile and treated with a solution of 0.8 g (6.4 mmol) oxalic acid dihydrate in 5 ml acetonitrile. The precipitate was collected and washed with diethyl ether to yield 1.34 g (18 %) of the title compound as a solid (m.p. 168-169 0C). 49. 6-(N,N-Dimethylaminocarbonyl)-4-(2-ethyl-6-methyl-benzylamino)-2-methyl- H-benzimidazole 0.7 g (1.25 mmol) 1-benzyloxymethyl-6-(N,N-dimethylaminocarbonyl)-4-(2-ethyl-6-methyl-benzy[amino) 2-methyl-I H-benzimidazole oxalate were partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic layer was separated and evaporated. The residue was dis solved in 15 ml methanol and hydrogenated over 0.3 g 10% Pd/C (70 oC, 1 bar H 2 ) for 2 h. The catalyst WO 2004/054984 PCT/EP2003/014069 50 was filtered off and the filtrate was evaporated. The residue was purified by column chromatography on silica gel using first dichloromethane:methanol (13:1), then ethyl acetate:triethylamine (9:1). Crystalliza tion from diisopropyl ether yielded 0.1 g (23 %) of the title compound as a solid (m.p. 228-230'C). 50. 6-(N,N-Dimethylaminocarbonyl)-4-(2-methoxycarbonylamino-6-methyl-benzylamino)-1,2 dimethyl-I H-benzimidazole To a suspension of 0.38 g (1.63 mmol) 4-amino-6-(N,N-dimethylaminocarbonyl)-1,2-dimethyl-1H benzimidazole and 0.37 g (1.71 mmol) 2-methoxycarbonylamino-6-methyl-benzyl chloride in 20 ml ace tone were added 0.35 g (3.26 mmol) sodium carbonate and 25 mg (0.16 mmol) sodium iodide. After 3 h stirring at ambient temperature, the reaction mixture was poured into 80 ml water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using tolu ene:dioxane:methanol (6:3.8:0.2) and crystallization from diisopropyl ether yielded 0.37 g (55 %) of the title compound as a colourless solid (m.p. 193-195 'C). 51.4-(trans-2,3-Dihydro-2-hydroxy-1-indenylamino)-6-(N,N-dimethylaminocarbonyl)-1 ,2 dimethyl-I H-benzimidazole To a suspension of 0.6 g (2.6 mmol) 4-amino-6-(N,N-dimethylaminocarbonyl)-1,2-dimethyl-lH benzimidazole and 1 g (7.7 mmol) 1,2-epoxyindane in 10 ml dioxane and 2 ml water was added one drop of triethylamine and the reaction mixture was stirred at 100 'C for 6 h. After cooling down, the mix ture was poured into 100 ml water and extracted with dichloromethane. The organic layer was sepa rated, washed with water, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using toluene:dioxane:methanol (6:3:1) and crystal lization from diisopropyl ether yielded 0.72 g (77 %) of the title compound as a colourless solid (m.p. 219-221 -C). 52. Ethyl 4-benzyloxy-1,2-dimethyl-IH-benzimidazole-6-carboxylate To a solution of 15.0 g (45.3 mmol) 4-benzyloxy-6-bromo-1,2-dimethyl-1H-benzimidazole in 200 ml ethanol and 50 ml triethylamine were added 1.53 g (6.8 mmol) palladium(ll) acetate and 5.35 g (20.4 mmol) triphenylphosphine. The mixture was transferred to an autoclave and carbonylated (10 bar car bon monoxide pressure, 100 oC) for 18 h. The reaction mixture was cooled down, evaporated and the residue was dissolved in dichloromethane. The organic layer was extracted with water, dried over an hydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate/n-heptane and activated charcoal yielded 12.3 g (84 %) of the title compound as a colourless solid (m.p. 152 'C). 53. Methyl 4-benzyloxy-1,2-dimethyl-IH-benzimidazole-6-carboxylate To a solution of 27.0 g (81 mmol) 4-benzyloxy-6-bromo-1,2-dimethyl-1H-benzimidazole in 340 ml methanol and 90 ml triethylamine were added 2.7 g (12 mmol) palladium(ll) acetate and 9.6 g (37 mmol) triphenylphosphine. The mixture was transferred to an autoclave and carbonylated (10 bar car bon monoxide pressure, 100 'C) for 16 h. The reaction mixture was cooled down, filtered and evapo- WO 2004/054984 PCT/EP2003/014069 51 rated. The residue was dissolved in dichloromethane, extracted with water, dried over anhydrous mag nesium sulphate and evaporated. The residue was dissolved in hot ethyl acetate and treated with acti vated charcoal. After filtration, the filtrate was evaporated to leave a dark brown solid which was purified by column chromatography on silica gel using dichloromethane:methanol (30:1) to yield 15.6 g (62 %) of the title compound as a grey solid (m.p. 166 *C). 54. 6-(1 -Aziridinylcarbonyl)-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1H-benzimidazole To a suspension of 1.0 g (3.1 mmol) 4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-IH-benzimidazole-6 carboxylic acid in 20 ml tetrahydrofuran and 10 ml N,N-dimethylformamide were added 0.9 g (5.6 mmol) N,N'-carbonyldiimidazole. After 2 h at 60 0C, the solution was cooled to 30 'C and 1.5 ml (29 mmol) aziridine were added in three portions over a period of 1.5 h. 50 ml water were added and the mixture was extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate and crystallization from ethyl acetate/n-heptane yielded 0.92 g (86 %) of the title compound as a colourless solid (m.p. 201-202 C). 55. 4-(2,6-Dimethyl-benzylamino)-1,2-dimethyl-6-(N-methylaminocarbonyl)-1H-benzimidazole To a suspension of 1.0 g (3.1 mmol) 4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-lH-benzimidazole-6 carboxylic acid in 20 ml tetrahydrofuran and 10 ml N,N-dimethylformamide were added 0.9 g (5.6 mmol) N,N'-carbonyldiimidazole. After 1.5 h at 60 0C, the solution was cooled down to 40 'C and 3.05 ml (6.1 mmol) methylamine (2M in tetrahydrofuran) were added. After 30 min, saturated aqueous am monium chloride was added and the mixture was extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate yielded 1.0 g (96 %) of the title compound as a colourless solid (m.p. 252-253 0C). 56. 4-(2,6-Dimethyl-benzylamino)-6-(N-2-hydroxyethyl-N-methylaminocarbonyl)-1 ,2-dimethyl-1 H benzimidazole To a suspension of 1.0 g (3.1 mmol) 4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1lH-benzimidazole-6 carboxylic acid in 45 ml dichloromethane and 10 ml N,N-dimethylformamide were added 1.9 g (5.9 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate (TBTU) and the mix ture was heated to 40 oC. After 1 h, 0.6 ml (8.0 mmol) 2-(methylamino)ethanol were added at ambient temperature. After 4 h, the reaction mixture was partitioned between 6N aqueous sodium hydroxide and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel using dichloro methane:methanol (13:1). Crystallization from acetone/diethyl ether yielded 0.77 g (65 %) of the title compound as a colourless solid.(m.p. 177-178 0C). 57. 4-(2,6-Dimethyl-benzylamino)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid hydrazide To a suspension of 1.0 g (3.1 mmol) 4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-lH-benzimidazole-6 carboxylic acid in 20 ml tetrahydrofuran and 10 ml N,N-dimethylformamide were added 0.9 g (5.6 WO 2004/054984 PCT/EP2003/014069 52 mmol) N,N'-carbonyldiimidazole. After 1.5 h at 60 OC, the solution was cooled down to 40 oC and 0.3 ml (9.4 mmol) hydrazine were added. After 1 h, the precipitate was collected and recrystallized from 2 propanol to yield 0.88 g (85 %) of the title compound as a colourless solid (m.p. 277-278 OC). 58.4-(2,6-Dimethyl-benzylamino)-6-hydroxymethyl-1,2-dimethyl-1H-benzimidazole To a suspension of 0.8 g (21 mmol) lithium aluminium hydride in 40 ml dried tetrahydrofuran was slowly added a solution of 4.0 g (11.4 mmol) ethyl 4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1 H benzimidazole-6-carboxylate in 20 ml dried tetrahydrofuran at 0 oC under a nitrogen atmosphere. After 2 h, an additional amount of 0.4 g (10.5 mmol) lithium aluminium hydride was added and stirring was continued at room temperature for 1 h. The reaction mixture was cautiously hydrolyzed with 0.3 ml wa ter, 0.6 ml 6N aqueous potassium hydroxide and 0.3 ml water. Anhydrous magnesium sulphate was added, the suspension was filtered through celite and washed with boiling dichloromethane. After addi tion of 50 g silica gel, the mixture was evaporated to dryness and the residue was put on a column and eluted with dichloromethane:methanol (20:1). Evaporation of the solvent left a solid, which was crystal lized from ethyl acetate/n-heptane to give 1.4 g (40 %) of the title compound as a colourless solid (m.p. 245-246 0C). 59.2-Cyclopropyl-4-(trans-2,3-dihydro-2-hydroxy-1-indenyloxy)-1-methyl-1H-benzimidazole-6 carboxylic acid To a suspension of 1.5 g (5.8 mmol) ethyl 2-cyclopropyl-4-hydroxy-1-methyl-1H-benzimidazole-6 carboxylate and 1.5 g (11.5 mmol) 1,2-epoxyindane in 18 ml ethanol and 5 ml water were added 1.6 ml triethylamine and the mixture was heated to 50 'C for 4 h. The cooled solution was partitioned between dichloromethane and saturated aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatog raphy on silica gel using dichloromethane:methanol (13:1) and crystallization from ethyl acetate/n heptane yielded 0.8 g of a solid, which was suspended in 20 ml dioxane and 4 ml 2N aqueous sodium hydroxide. After 3 h at 80 0C, the reaction mixture was cooled down and the pH was adjusted to pH = 6 by adding 6N hydrochloric acid. After addition of 50 g silica gel, the mixture was evaporated to dryness and the residue was put on a column and eluted with dichloromethane:methanol (10:1). Evaporation of the solvent left a solid, which was crystallized from ethyl acetate/diethyl ether to give 0.68 g (32 %) of the title compound (m.p. 132-134 0C). 60. 2-Cyclopropyl-4-(trans-2,3-dihydro-2-hydroxy-1-indenyloxy)-6-(N,N-dimethylaminocarbonyl) 1-methyl-IH-benzimidazole To a suspension of 0.67 g (1.8 mmol) 2-cyclopropyl-4-(trans-2,3-dihydro-2-hydroxy-1-indenyloxy)-l methyl-lH-benzimidazole-6-carboxylic acid in 30 ml dichloromethane and 7 ml N,N-dimethylformamide were added 1.0 g (3.1 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate (TBTU) and the mixture was heated to 40 *C. After 1 h, 2.3 ml (11.4 mmol) dimethylamine (5M in tetra hydrofuran) were added at ambient temperature. After 30 min, the reaction mixture was partitioned between 2N aqueous sodium hydroxide and dichloromethane. The organic layer was separated, dried WO 2004/054984 PCT/EP2003/014069 53 over anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatog raphy on silica gel using dichloromethane:methanol (13:1) to yield 0.63 g (87 %) of a colourless foam. 61. 6-(N,N-Dimethylaminocarbonyl)-1,2-dimethyl-4-(2-methyl-benzylamino)-1 H-benzimidazole To a solution of 1.2 g (3.5 mmol) 6-bromo-1,2-dimethyl-4-(2-methyl-benzylamino)-1H-benzimidazole in 55 ml dimethylamine (5M in tetrahydrofuran) were added 0.24 g (0.3 mmol) bis(triphenylphosphine) palladium(ll) chloride. The mixture was transferred to an autoclave and carbonylated (5 bar carbon monoxide pressure, 100 OC) for 16 h. The reaction mixture was cooled down and filtered. The filtrate was partitioned between dichioromethane and water. The organic layer was separated, dried over an hydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using toluene:dioxane:methanol (6:3.9:0.1) and crystallization from ethyl acetate/n-heptane yielded 0.37 g (31 %) of the title compound as a colourless solid (m.p. 158-159 0C). 62. 6-(N,N-Dimethylaminocarbonyl)-4-(2,4-dimethyl-furan-3-yi-methylamino)-1 ,2-dimethyl-1H benzimidazole To a solution of 0.4 g (1.15 mmol) 6-bromo-4-(2,4-dimethyl-furan-3-yl-methylamino)-1,2-dimethyl-1H benzimidazole in 20 ml dimethylamine (2M in tetrahydrofuran) were added 40 mg (0.17 mmol) palla dium(ll) acetate and 0.12 g (0.46 mmol) triphenylphosphine. The mixture was transferred to an auto clave and carbonylated (6 bar carbon monoxide pressure, 120 oC) for 16 h. The reaction mixture was cooled down and filtered. The filtrate was partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (20:1) and crystalliza tion from ethyl acetate/n-heptane yielded 0.1 g (26 %) of the title compound as a colourless solid (m.p. 163-164 0C). 63. 7-(2,6-Dimethyl-benzylamino)-2,3-dimethyl-3H-benzimidazole-5-sulfonic acid dimethylamide A suspension of 0.5 g (1.86 mmol) 7-amino-2,3-dimethyl-3H-benzimidazole-5-sulfonic acid dimethyla mide and 0.3 g (1.96 mmol) 2,6-dimethyl-benzyl chloride was stirred at room temperature and 0.08 g (2.05 mmol) sodium hydride (60 % dispersion in mineral oil) were added. The reaction mixture was warmed to 45 0C and an additional amount of 0.3 g (1.96 mmol) 2,6-dimethyl-benzyl chloride and 0.13 g (3.25 mmol) sodium hydride were added in two portions over a period of 1.5 h. The mixture was stirred for 16 h at 40 0C, cooled down and partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (75:25) and crystalliza tion from ethyl acetate/n-heptane yielded 0.35 g (49 %) of the title compound as a colourless solid (m.p. 237-238 0C). 64. Ethyll-benzyloxymethyl-4-(2,6-dimethyl-benzylamino)-2-methyl-1H-benzimidazole-6 carboxylate To a solution of 6.5 g (14.2 mmol) 1-benzyloxymethyl-6-bromo-4-(2,6-dimethyl-benzylamino)-2-methyl 1H-benzimidazole in 125 ml ethanol and 25 ml triethylamine were added 1.0 g (1.36 mmol) WO 2004/054984 PCT/EP2003/014069 54 bis(triphenylphosphine)palladium(ll) chloride. The mixture was transferred to an autoclave and carbon ylated (6 bar carbon monoxide pressure, 100 'C) for 16 h. The reaction mixture was cooled down and filtered. The filtrate was partitioned between dichloromethane and water. The organic layer was sepa rated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (100:1) and crystallization from ethyl acetate/n-heptane yielded 5.3 g (82 %) of the title compound as a colourless solid (m.p. 155-156 0C). 65. 1 -Benzyloxymethyl-4-(2,6-dimethyl-benzylamino)-2-methyl-1H-benzimidazole-6-carboxylic Acid To a suspension of 5.0 g (10.9 mmol) ethyl 1-benzyloxymethyl-4-(2,6-dimethyl-benzylamino)-2-methyl 1H-benzimidazole-6-carboxylate in 30 ml dioxane were added 15 ml 2N aqueous sodium hydroxide. After 2 h at 90 oC, the reaction mixture was cooled down and the pH was adjusted to pH = 7 by adding 6N hydrochloric acid. After addition of 50 g silica gel, the mixture was evaporated to dryness and the residue was put on a column and eluted with dichloromethane:methanol (13:1). Evaporation of the sol vent left a solid, which was crystallized from diethyl ether to give 4.36 g of the title compound which was used without further purification for the next step. 66. 1-BenzyIoxymethyl-6-(NN-dimethylaminocarbonyl)-4-(2,6-dimethylbenzylamino)-2-methyl IH-benzimidazole To a suspension of 3.0 g (7 mmol, crude product) 1-benzyloxymethyl-4-(2,6-dimethyl-benzylamino)-2 methyl-1H-benzimidazole-6-carboxylic acid in 30 ml tetrahydrofuran and 15 ml N,N-dimethylformamide were added 1.97 g (12.2 mmol) N,N'-carbonyldiimidazole. After 2 h at 60 'C, the solution was cooled down to 40 oC and 5.0 ml (25 mmol) dimethylamine (5M in tetrahydrofuran) were added. After 30 min, saturated aqueous ammonium chloride was added and the mixture was extracted with dichloro methane. The organic layer was separated, dried over anhydrous magnesium sulphate and evapo rated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petro leum ether (75:25) yielded 2.68 g (84 %) of the title compound as a colourless foam (m.p. 55-56 0C). 67. 6-(N,N-Dimethylaminocarbonyl)-4-(2,6-dimethyl-benzylamino)-2-methyl-1 H-benzimidazole A suspension of 2.4 g (7.1 mmol) 1-benzyloxymethyl-6-(N,N-dimethylaminocarbonyl)-4-(2,6-dimethyl benzylamino)-2-methyl-lH-benzimidazole, 4.5 g (71 mmol) ammonium formate and 0.5 g palladium on charcoal (10 %) in 50 ml ethanol was heated to reflux. After 2 h, the mixture was filtered through celite and evaporated. The residue was partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate/n-heptane yielded 1.4 g (59 %) of the title compound as a colour less solid (m.p. 203 oC). 68. I-Benzyloxymethyl-6-(N-methylaminocarbonyl)-4-(2,6-dimethyl-benzylamino)-2-methyl-1H benzimidazole To a suspension of 1.3 g (3 mmol, crude product) 1-benzyloxymethyl-4-(2,6-dimethyl-benzylamino)-2 methyl-1H-benzimidazole-6-carboxylic acid in 20 ml tetrahydrofuran and 10 ml N,N-dimethylformamide WO 2004/054984 PCT/EP2003/014069 55 were added 0.8 g (4.9 mmol) N,N'-carbonyldiimidazole. After 2.5 h at 60 'C, the solution was cooled down to 40 0C and 5.0 ml (10 mmol) methylamine (2M in tetrahydrofuran) were added. After 1 h, satu rated aqueous ammonium chloride was added and the mixture was extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purifica tion of the residue by crystallization from ethyl acetate/n-heptane yielded 0.91 g (71 %) of the title com pound as a colourless solid (m.p. 215-216 'C). 69. 4-(2,6-Dimethyl-benzylamino)-6-(N-methylaminocarbonyl)-2-methyl-1 H-benzimidazole A suspension of 0.85 g (1.92 mmol) 1-benzyloxymethyl-6-(N-methylaminocarbonyl)-4-(2,6-dimethyl benzylamino)-2-methyl-1H-benzimidazole, 2.5 g (40 mmol) ammonium formate and 0.26 g palladium on charcoal (10 %) in 45 ml ethanol was heated to reflux. After 1.5 h, the mixture was filtered through celite and evaporated. The residue was partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate/n-heptane yielded 0.47 g (76 %) of the title compound as a colourless solid (m.p. 298 OC). 70. 6-(N,N-Dimethylaminocarbonyl)-4-(2-hydroxymethyl-6-methyl-benzylamino)-1,2-dimethyl-1H benzimidazole To a solution of 0.45 g (1.2 mmol) 6-bromo-4-(2-hydroxymethyl-6-methyl-benzylamino)-1,2-dimethyl 1H-benzimidazole in 5 ml dimethylamine and 15 ml tetrahydrofuran were added 0.125 g (0.18 mmol) bis(triphenylphosphine)palladium(ll) chloride. The mixture was transferred to an autoclave and carbon ylated (6 bar carbon monoxide pressure, 120 0C) for 16 h. The reaction mixture was cooled down and filtered. The filtrate was partitioned between dichloromethane and saturated aqueous ammonium chlo ride. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (20:1) and crystallization from ethyl acetate/n-heptane yielded 0.07 g (15 %) of the title compound as a colourless solid (m.p. 197-198 oC). 71. 6-Cyano-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-IH-benzimidazole A suspension of 6.0 g (16.8 mmol) 6-bromo-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-lH benzimidazole, 2.1 g (17.9 mmol) zinc cyanide and 1.94 g (1.68 mmol) tetrakis(triphenylphosphine)palladium in 50 ml degassed N,N-dimethylformamide was heated to 100 oC. After 40 min, the reaction mixture was cooled down, poured into 300 ml saturated aqueous ammonium chloride and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (100:1) and crystallization from ethyl acetate yielded 4.56 g of the title compound as a colourless solid which was used without further purification for the next step.
WO 2004/054984 PCT/EP2003/014069 56 72.6-(4,5-Dihydro-1H-imidazol-2-yl)-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-I H-benzimida zole A suspension of 0.5 g (1.64 mmol) 6-cyano-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1lH-benzimida zole and a catalytic amount of phosphorus pentasulfide in 5 ml ethylenediamine was heated to 120 oC. After I h, the reaction mixture was cooled down and partitioned between water and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purifica tion of the residue by crystallization from diethyl ether yielded 0.54 g (90 %) of the title compound as a yellow solid (m.p. 273-274 °C). 73. 6-(4,5-Dihydro-l-methyl-I H-imidazol-2-yl)-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-I H benzimidazole A suspension of 0.25 g (0.82 mmol) 6-cyano-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1H-benzimida zole and a catalytic amount of phosphorus pentasulfide in 2.5 ml N-methyl-ethylenediamine was heated to 120 0C. After 1 h, the reaction mixture was cooled down and partitioned between water and di chloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloro methane:methanol (4:1) and crystallization from diethyl ether yielded 0.11 g (37 %) of the title com pound as a colourless solid (m.p. 118-119 0C). 74. 6-(4,5-Dihydro-oxazol-2-yl)-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-IH-benzimidazole A suspension of 0.5 g (1.64 mmol) 6-cyano-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-lH benzimidazole and 0.54 g (3.9 mmol) zinc chloride in 5 ml ethanolamine was heated to 140 0C. After 3.5 h, the reaction mixture was cooled down and partitioned between saturated aqueous ammonium chloride and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate and crystallization from ethyl acetate/diethyl ether yielded 0.25 g (42 %) of the title compound as a colourless solid (m.p. 235 oC). 75. 4-(2,6-Dimethyl-benzylamino)-N-hydroxy-1,2-dimethyl-I H-benzimidazole-6-carboxamidine A suspension of 0.5 g (1.64 mmol) 6-cyano-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-lH benzimidazole, 0.67 g (9.6 mmol) hydroxylamine hydrochloride and 1.04 g (9.8 mmol) sodium carbon ate in 10 ml N,N-dimethylformamide was heated to 110 'C. After 7 h, the reaction mixture was cooled down and partitioned between saturated aqueous ammonium chloride and dichloromethane. The or ganic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (13:1) and crystal lization from acetone yielded 0.39 g (71 %) of the title compound as a colourless solid (m.p. 230 0C). 76. 6-Bromo-4-(2,6-dimethyl-benzylamino)-1l-hydroxy-2-methyl-1H-benzimidazole To a suspension of 4.0 g (16.5 mmol) 4-amino-6-bromo-1-hydroxy-2-methyl-1H-benzimidazole and 2.5 g (18.6 mmol) 2,6-dimethyl-benzaldehyde in 80 ml methanol were added 3.1 g (49.3 mmol) sodium cyanoborohydride in small portions and the pH was maintained at pH = 3 by gradual addition of metha- WO 2004/054984 PCT/EP2003/014069 57 nolic hydrogen chloride. After 3 h, the reaction mixture was hydrolyzed with saturated aqueous sodium hydrogen carbonate and partitioned between dichloromethane and water. The organic layer was sepa rated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystal lization from acetone yielded 2.4 g (40 %) of the title compound as a colourless solid (m.p. 277 *C). 77. 6-Bromo-4-(2,6-dimethyl-benzylamino)-1-methoxy-2-methyl-1H-benzimidazole To a suspension of 0.36 g (1.0 mmol) 6-bromo-4-(2,6-dimethyl-benzylamino)-1l-hydroxy-2-methyl-1lH benzimidazole and 0.3 g (2.2 mmol) potassium carbonate in 3 ml acetone were added 0.7 ml (1.12 mmol) of methyl iodide (1.6M in acetone). After 4 h, the reaction mixture was partitioned between di chloromethane and saturated aqueous ammonium chloride. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from diethyl ether/n-heptane yielded 0.2 g (53 %) of the title compound as a colourless solid (m.p. 171-172 OC). 78. Ethyl 4-(2,6-dimethyl-benzylamino)-1l-methoxy-2-methyl-1H-benzimidazole-6-carboxylate To a solution of 1.5 g (4.0 mmol) 6-bromo-4-(2,6-dimethyl-benzylamino)-1 -methoxy-2-methyl-1 H benzimidazole in 60 ml ethanol and 3.3 ml triethylamine were added 0.35 g (0.5 mmol) bis(triphenylphosphine)palladium(ll) chloride. The mixture was transferred to an autoclave and carbon ylated (6 bar carbon monoxide pressure, 120 'C) for 16 h. The reaction mixture was cooled down and filtered through celite. The filtrate was evaporated and partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purifica tion of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (1:1) yielded 0.44 g (29 %) of the title compound as a colourless solid (m.p. 165-166 'C). 79.4-(2,6-Dimethyl-benzylamino)-1-methoxy-2-methyl-1H-benzimidazole-6-carboxylic acid To a suspension of 0.43 g (1.17 mmol) ethyl 4-(2,6-dimethyl-benzylamino)-1-methoxy-2-methyl-1H benzimidazole-6-carboxylate in 10 ml dioxane were added 2 ml 2N aqueous sodium hydroxide. After 8 h at 80 'C and stirring overnight at ambient temperature, the reaction mixture was cooled down and the pH was adjusted to pH = 7 by adding 2N hydrochloric acid. After addition of 25 g silica gel, the mixture was evaporated to dryness and the residue was put on a column and eluted with dichloro methane: methanol (13:1). Evaporation of the solvent left a solid, which was crystallized from acetone to give 0.3 g (75 %) of the title compound as a colourless solid (m.p. 248-249 oC). 80. 6-(N,N-Dimethylamino-carbonyl)-4-(2,6-dimethyl-benzylamino)-1 -methoxy-2-methyl-1H benzimidazole To a suspension of 0.28 g (0.8 mmol) 4-(2,6-dimethyl-benzylamino)-1-methoxy-2-methyl-1H benzimidazole-6-carboxylic acid in 15 ml dichloromethane and 3.5 ml N,N-dimethylformamide were added 0.5 g (1.6 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate (TBTU). After 1 h at 40 'C, 2.4 ml (4.8 mmol) dimethylamine (2M in tetrahydrofuran) were added at ambient temperature. After 30 min, the reaction mixture was partitioned between 2N aqueous sodium hydroxide and dichloromethane. The organic layer was separated, dried over anhydrous magnesium WO 2004/054984 PCT/EP2003/014069 58 sulphate and evaporated. The residue was purified by crystallization from diethyl ether to yield 0.24 g (80 %) of the title compound as a colourless solid (m.p. 128-129 °C). 81. 2-Acetoxymethyl-6-bromo-4-(2,6-dimethyl-benzylamino)-l-methyl-1H-benzimidazole A suspension of 1.0 g (3.35 mmol) 2-acetoxymethyl-4-amino-6-bromo-1l-methyl-IH-benzimidazole, 0.54 g (3.5 mmol) 2,6-dimethyl-benzyl chloride, 0.93 g (6.7 mmol) potassium carbonate and a catalytic amount of potassium iodide in 15 ml acetonitrile was heated to 70 'C. After 4 h, a further amount of 0.27 g (1.75 mmol) 2,6-dimethyl-benzyl chloride were added and stirring was continued for 2 h. The reaction mixture was poured into 50 ml water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (7:3) and crystalliza tion from ethyl acetate/n-heptane yielded 0.58 g (42 %) of the title compound as a colourless solid (m.p. 188-190 0C). 82. 6-(N,N-Dimethylaminocarbonyl)-4-(2,6-dimethyl-benzylamino)-2-hydroxymethyl-1-methyl-1 H benzimidazole To a solution of 2.0 g (4.8 mmol) 2-acetoxymethyl-6-bromo-4-(2,6-dimethyl-benzylamino)-1l-methyl-lH benzimidazole in 30 ml dimethylamine (2M in tetrahydrofuran) were added 0.67 g (0.95 mmol) bis(triphenylphosphine)palladium(ll) chloride. The mixture was transferred to an autoclave and carbon ylated (6 bar carbon monoxide pressure, 120 'C) for 25 h. The reaction mixture was cooled down and filtered. The filtrate was partitioned between saturated aqueous ammonium chloride and dichloro methane. The organic layer was separated, dried over anhydrous magnesium sulphate and evapo rated. The residue was dissolved in 20 ml methanol and 0.1 g cesium carbonate were added. The mix ture was refluxed for 30 min, cooled down and evaporated. Purification of the residue by column chro matography on silica gel using dichloromethane:methanol (13:1) and crystallization from ethyl acetate yielded 0.5 g (26 %) of the title compound as a colourless solid (m.p. 171-172 'C). 83. 6-(N,N-Dimethylaminocarbonyl)-4-(2-ethyl-6-methyl-benzylamino)-2-hydroxymethyl-1-methyl 1H-benzimidazole To a solution of 0.5 g (1.28 mmol) 6-bromo-4-(2-ethyl-6-methyl-benzylamino)-2-hydroxymethyl-1 methyl-iH-benzimidazole in 10 ml dimethylamine (2M in tetrahydrofuran) and 20 ml tetrahydrofuran were added 0.03 g (0.128 mmol) palladium(ll) acetate and 0.2 g (0.77 mmol) triphenylphosphine. The mixture was transferred to an autoclave and carbonylated (6 bar carbon monoxide pressure, 120 0C) for 16 h. The reaction mixture was cooled down, poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate and crystallization from ethyl ace tate/diisopropyl ether yielded 0.28 g (58 %) of the title compound as a colourless solid (m.p. 138-141
°C).
WO 2004/054984 PCT/EP2003/014069 59 84. 4-(2,6-Dimethyl-benzylamino)-6-(5-ethyl-[1,3,4]oxadiazol-2yl)-1,2-dimethyl-1H-benzimidazole 0.1 g (0.3 mmol) 4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1 H-benzimidazole-6-carboxylic acid hy drazide were suspended in 5 ml triethyl orthopropionate. After 1 h at 140 'C, the reaction mixture was cooled down and partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by crystallization from n-heptane yielded 0.08 g (71 %) of the title compound as a yellow solid (m.p. 246-247 oC). 85. 4-(2,6-Dimethyl-benzylamino)-6-(5-methyl-[1,3,4]oxadiazol-2yl)-1,2-dimethyl-1H-benzimida zole 0.5 g (1.48 mmol) 4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1lH-benzimidazole-6-carboxylic acid hy drazide were suspended in 7 ml triethyl orthoacetate. After 2 h at 140 'C, the reaction mixture was cooled down and partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chro matography on silica gel using dichloromethane:methanol (20:1) and crystallization from diethyl ether yielded 0.2 g (37 %) of the title compound as a colourless solid (m.p. 256-257 oC). 86. Ethyl 4-benzyloxy-2-cyclopropyl-1-methyl-I H-benzimidazole-6-carboxylate To a solution of 2.9 g (8.1 mmol) 4-benzyloxy-6-bromo-2-cyclopropyl-1-methyl-1H-benzimidazole in 100 ml ethanol and 7 ml triethylamine were added 0.6 g (0.86 mmol) bis(triphenylphosphine)palladium(ll) chloride. The mixture was transferred to an autoclave and carbonylated (10 bar carbon monoxide pres sure, 100 'C) for 18 h. The reaction mixture was cooled down, filtered and evaporated. The residue was dissolved in dichloromethane and extracted with water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatog raphy on silica gel using toluene:dioxane (10:1) and crystallization from ethyl acetate/light petroleum ether yielded 2.33 g (83 %) of the title compound as a colourless solid (m.p. 120 oC). The following compounds can be obtained in an analogous manner using analogous reaction steps as described in the examples above: a) 6-(N,N-Dimethylaminocarbonyl)-2-(N,N-dimethylamino)-4-(2,6-dimethyl-benzylamino)-1l-methyl-lH benzimidazole b) 6-(N,N-Dimethylaminocarbonyl)-2-(N,N-dimethylamino)-4-(2-ethyl-6-methyl-benzylamino)-1l-methyl 1H-benzimidazole WO 2004/054984 PCT/EP2003/014069 60 Commercial utility The compounds of the formula 1 and 2 and their salts have valuable pharmacological properties which make them commercially utilizable. In particular, they exhibit marked inhibition of gastric acid secretion and an excellent gastric and intestinal protective action in warm-blooded animals, in particular humans. In this connection, the compounds according to the invention are distinguished by a high selectivity of action, an advantageous duration of action, a particularly good enteral activity, the absence of signifi cant side effects and a large therapeutic range. "Gastric and intestinal protection" in this connection is understood as meaning the prevention and treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, gastric ulcer, duodenal ulcer, gastritis, hyperacidic or medicament related functional dyspepsia), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, medicaments (e.g. certain antiinflammatories and antirheumatics), chemicals (e.g. ethanol), gastric acid or stress situations. In their excellent properties, the compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art in various models in which the antiulcerogenic and the antisecretory properties are determined. On account of these properties, the compounds of the formula 1 and 2 and their pharmacologically acceptable salts are outstandingly suitable for use in hu man and veterinary medicine, where they are used, in particular, for the treatment and/or prophylaxis of disorders of the stomach and/or intestine. A further subject of the invention are therefore the compounds according to the invention for use in the treatment and/or prophylaxis of the abovementioned diseases. The invention likewise includes the use of the compounds according to the invention for the production of medicaments which are employed for the treatment and/or prophylaxis of the abovementioned diseases. The invention furthermore includes the use of the compounds according to the invention for the treat ment and/or prophylaxis of the abovementioned diseases. A further subject of the invention are medicaments which comprise one or more compounds of the formula 1 and/or their pharmacologically acceptable salts. The medicaments are prepared by processes which are known per se and familiar to the person skilled in the art. As medicaments, the pharmacologically active compounds according to the invention (= ac tive compounds) are either employed as such, or preferably in combination with suitable pharmaceuti cal auxiliaries or excipients in the form of tablets, coated tablets, capsules, suppositories, patches (e.g. as TTS), emulsions, suspensions or solutions, the active compound content advantageously being WO 2004/054984 PCT/EP2003/014069 61 between 0.1 and 95% and it being possible to obtain a pharmaceutical administration form exactly adapted to the active compound and/or to the desired onset and/or duration of action (e.g. a sustained release form or an enteric form) by means of the appropriate selection of the auxiliaries and excipients. The auxiliaries and excipients which are suitable for the desired pharmaceutical formulations are known to the person skilled in the art on the basis of his/her expert knowledge. In addition to solvents, gel forming agents, suppository bases, tablet auxiliaries and other active compound excipients, it is possi ble to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (e.g. cyclodextrins). The active compounds can be administered orally, parenterally or percutaneously. In general, it has proven advantageous in human medicine to administer the active compound(s) in the case of oral administration in a daily dose of approximately 0.01 to approximately 20, preferably 0.05 to 5, in particular 0.1 to 1.5, mg/kg of body weight, if appropriate in the form of several, preferably 1 to 4, individual doses to achieve the desired result. In the case of a parenteral treatment, similar or (in par ticular in the case of the intravenous administration of the active compounds), as a rule, lower doses can be used. The establishment of the optimal dose and manner of administration of the active com pounds necessary in each case can easily be carried out by any person skilled in the art on the basis of his/her expert knowledge. If the compounds according to the invention and/or their salts are to be used for the treatment of the abovementioned diseases, the pharmaceutical preparations can also contain one or more pharmaco logically active constituents of other groups of medicaments, for example: tranquillizers (for example from the group of the benzodiazepines, for example diazepam), spasmolytics (for example, bietamiver ine or camylofine), anticholinergics (for example, oxyphencyclimine or phencarbamide), local anesthet ics, (for example, tetracaine or procaine), and, if appropriate, also enzymes, vitamins or amino acids. To be emphasized in this connection is in particular the combination of the compounds according to the invention with pharmaceuticals which inhibit acid secretion, such as, for example, H 2 blockers (e.g. cimetidine, ranitidine), H /K' ATPase inhibitors (e.g. omeprazole, pantoprazole), or further with so called peripheral anticholinergics (e.g. pirenzepine, telenzepine) and with gastrin antagonists with the aim of increasing the principal action in an additive or super-additive sense and/or of eliminating or of decreasing the side effects, or further the combination with antibacterially active substances (such as, for example, cephalosporins, tetracyclines, penicillins, macrolides, nitroimidazoles or alternatively bismuth salts) for the control of Helicobacter pylori. Suitable antibacterial co-components which may be mentioned are, for example, mezlocillin, ampicillin, amoxicillin, cefalothin, cefoxitin, cefotaxime, imipenem, gentamycin, amikacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromy cin and combinations thereof (for example clarithromycin + metronidazole).
WO 2004/054984 PCT/EP2003/014069 62 In view of their excellent gastric and intestinal protection action, the compounds of formula 1 are suited for a free or fixed combination with those medicaments (e.g. certain antiinflammatories and antirheu matics, such as NSAIDs), which are known to have a certain ulcerogenic potence.
WO 2004/054984 PCT/EP2003/014069 63 Pharmacology The excellent gastric protective action and the gastric acid secretion-inhibiting action of the compounds according to the invention can be demonstrated in investigations on animal experimental models. The compounds according to the invention investigated in the model mentioned below have been provided with numbers which correspond to the numbers of these compounds in the examples. Testing of the secretion-inhibiting action on the perfused rat stomach In Table A which follows, the influence of the compounds according to the invention on the pentagastrin-stimulated acid secretion of the perfused rat stomach after intraduodenal administration in vivo is shown. Table A Biological Data No. Dose Inhibition of (pmol/kg) acid secretion i.d. (%) 8 1 > 50 10 1 > 50 11 1 > 50 13 1 > 50 19 1 > 50 35 1 > 50 38 1 > 50 40 1 > 50 41 1 > 50 42 1 > 50 43 1 > 50 44 1 > 50 45 1 > 50 46 1 > 50 49 1 > 50 55 1 > 50 Methodology The abdomen of anesthetized rats (CD rat, female, 200-250 g; 1.5 g/kg i.m. urethane) was opened after tracheotomy by a median upper abdominal incision and a PVC catheter was fixed transorally in the esophagus and another via the pylorus such that the ends of the tubes just projected into the gastric lumen. The catheter leading from the pylorus led outward into the right abdominal wall through a side opening.
WO 2004/054984 PCT/EP2003/014069 64 After thorough rinsing (about 50-100 ml), warm (370C) physiological NaCI solution was continuously passed through the stomach (0.5 ml/min, pH 6.8-6.9; Braun-Unita I). The pH (pH meter 632, glass elec trode EA 147; 4 = 5 mm, Metrohm) and, by titration with a freshly prepared 0.01N NaOH solution to pH 7 (Dosimat 665 Metrohm), the secreted HCI were determined in the effluent in each case collected at an interval of 15 minutes. The gastric secretion was stimulated by continuous infusion of 1 pg/kg (= 1.65 ml/h) of i.v. pentagastrin (left femoral vein) about 30 min after the end of the operation (i.e. after determination of 2 preliminary fractions). The substances to be tested were administered intraduodenally in a 2.5 ml/kg liquid volume 60 min after the start of the continuous pentagastrin infusion. The body temperature of the animals was kept at a constant 37.8-38 0 C by infrared irradiation and heat pads (automatic, stepless control by means of a rectal temperature sensor).

Claims (12)

1. A compound of the formula 1 R2 / R3N N NJ R 1 (1) Yx in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminol-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31R32, the group SO 2 -NR31R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist ing of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1 -4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, X is O (oxygen) or NH and WO 2004/054984 PCT/EP2003/014069 66 Y has either the meaning -CH 2 -Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp R4 R5 (gP) z wherein Z has the meaning -CHR8- or-CHR8-CHR9 where in, Ar andlor in the group gp R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo gen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C alkoxy-1 -4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7is hydrogen, 1-4C-alkyl or halogen, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1 4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1 -4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1 4C-alkylcarbonyloxy, and wherein WO 2004/054984 PCT/EP2003/014069 67 aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes -CH 2 -Ar and R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-1-4C-alkyl, or a salt thereof.
2. A compound as claimed in claim 1, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl or hydroxy-1-4C alkyl, R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminol-4C-alkylcarbonyl, hydroxy-1-4C-alkyl or fluoro-2-4C-alkyl, R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl R32 is hydrogen, 1-7C-alkyl, hydroxy-l-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, X is O (oxygen) or NH and Y has either the meaning -CH 2 -Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp R4 R5 / (gp)0 z wherein Z has the meaning -CHR8- or-CHR8-CHR9 where in Ar and/or in the group gp WO 2004/054984 PCT/EP2003/014069 68 R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo gen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7is hydrogen, 1-4C-alkyl or halogen, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-l1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1 -4C-alkylcarbonyloxy or 1-4C-alkoxy-1 -4C-alkoxycarbonylamino, R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1 -4C-alkylcarbonyloxy or 1-4C-alkoxy-1 -4C-alkoxycarbonylamino and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes -CH 2 -Ar, or a salt thereof.
3. A compound as claimed in claim 1, characterized by the formula la R2 / R3 N I / RI N rX (1a) Ar in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-l1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1 -4C-alkyl WO 2004/054984 PCT/EP2003/014069 69 R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminol-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C alkoxy-1-4C-alkyl, 1-4C-alkoxy-l1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31R32, the group SO 2 -NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist ing of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-l1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, X is O (oxygen) or NH and Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, ben zimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, where R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halo gen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C alkoxy-1 -4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7is hydrogen, 1-4C-alkyl or halogen, WO 2004/054984 PCT/EP2003/014069 70 and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when Y denotes -CH 2 -Ar and R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-l-4C-alkyl, or a salt thereof.
4. A compound as claimed in claim 1, characterized by the formula lb R2 R3 N / RI R4 . N R5 / X (1 b) z in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-l-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1 4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-l1-4C-alkyl, hydroxy-l1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-l-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-l1-4C-alkyl, 1-4C-alkoxycarbonyl, mono- or di-l1-4C-alkylaminol-4C-alkylcarbonyl, hydroxy-l1-4C-alkyl, fluoro-2-4C-alkyl, aryl-l1-4C alkoxy-l-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-l-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-l-4C-alkyl, 1-4C alkoxy-l1-4C-alkyl, 1-4C-alkoxy-l1-4C-alkoxy-1-4C-alkyl, fluoro-l1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31R32,, the group SO 2 -NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-l-4C-alkyl, 1-4C-alkoxy-l-4C-alkyl or 3-7C cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-l1-4C-alkyl or 1-4C-alkoxy-l1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist ing of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroisoxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbo nyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-l1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-l1-4C-alkoxy, trifluoromethyl, nitro, WO 2004/054984 PCT/EP2003/014069 71 amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hy droxy, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-l1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hy droxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-I-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1 4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O (oxygen) or NH and Z has the meaning -CHR8- or-CHR8-CHR9 where R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1 4C-alkylcarbonyloxy, R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3 7C-cycloalkoxy, 3-7C-cycloalkyl-l-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1 4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxy and cyano, or a salt thereof.
5. A compound of formula la as claimed in claim 3, characterized by the formula la-1 WO 2004/054984 PCT/EP2003/014069 72 R2 / R3 N / RI N X (la-1) R5 R4 where R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R2 is hydrogen,1-4C-alkyl, hydroxy, 1-4C-alkoxy or aryl-1-4C-alkoxy-1-4C-alkyl R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-l-4C-alkyl, cyano, the group -CO NR31R32, the group SO 2 -NR31 R32 or the group Het, where R31 is hydrogen, 1-7C-alkyl, hydroxy-l-4C-alkyl, 1-4C-alkoxy-l-4C-alkyl, 3-7C-cycloalkyl or amino and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consist ing of oxadiazol, dihydrooxazol and dihydroimidazol, where R33 is hydrogen or 1-4C-alkyl, R34 is hydrogen or 1-4C-alkyl R35 is hydrogen or 1-4C-alkyl R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoromethyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino or 1 4C-alkoxy-1-4C-alkoxycarbonylamino, R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and X is O (oxygen) or NH, or a salt thereof.
6. A compound of formula lb as claimed in claim 4, characterized by the formula lb-1 WO 2004/054984 PCT/EP2003/014069 73 R2 / R3 N I / RI R4 N) N R5 / ' X (lb-1) R8 in which R1 is 1-4C-alkyl or 3-7C-cycloalkyl, R2 is hydrogen or 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-l-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen or 1-4C-alkyl, R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3 7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C alkoxycarbonylamino or 1-4C-alkoxy-l1-4C-alkylcarbonyloxy X is O (oxygen) or NH, or a salt thereof.
7. A compound of the formula lb-1 as claimed in claim 6 in which R1 is 1-4C-alkyl, R2 is hydrogen or 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-l -4C-alkyl, 1-4C-alkoxy-1 -4C-alkoxy-1 -4C-alkyl or the group -CO-NR31 R32, where R31 is hydrogen, 1-7C-alkyi, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1 -4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen, 1-7C-alkyl, hydroxy-l-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where WO 2004/054984 PCT/EP2003/014069 74 R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen, R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C alkoxy, hydroxy-l1-4C-alkoxy, 1-4C-alkoxy-l1-4C-alkoxy, 1-4C-alkoxy-l1-4C-alkoxy-1-4C-alkoxy, 3 7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-l1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C alkoxycarbonylamino, mono- or di-l1-4C-alkylamino-l1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C alkoxycarbonylamino or 1-4C-alkoxy-l1-4C-alkylcarbonyloxy X is O (oxygen) or NH, or a salt thereof.
8. A compound of the formula la-1 as claimed in claim 5, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, R4 is 1-4C-alkyl or 1-4C-alkylcarbonylamino, R5 is 1-4C-alkyl, X is O (oxygen) or NH, or a salt thereof.
9. The compound 6-(N,N-Dimethylaminocarbonyl)-4-(2-ethyl-6-methyl-benzylamino)-l,2-dimethyl-IH benzimidazole or a salt thereof.
10. The compound 6-(N,N-Dimethylaminocarbonyl)-4-(2,6-dimethyl-benzylamino)-1,2-dimethyl-1H benzimidazole or a salt thereof.
11. A medicament comprising a compound as claimed in claim 1 and/or a pharmacologically accept able salt thereof together with customary pharmaceutical auxiliaries and/or excipients.
12. The use of a compound as claimed in claim 1 and its pharmacologically acceptable salts for the prevention and treatment of gastrointestinal disorders.
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